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For an update on what medical science is doing to fight the global HIV/AIDS pandemic, read a Parade article by NIH Director Francis S. Collins and NIAID Director Anthony S. Fauci, AIDS in 2010: How We're Living with HIV .

Over the past several decades, researchers have learned a lot about the human immunodeficiency virus (HIV) and the disease it causes, acquired immunodeficiency syndrome (AIDS). But still more research is needed to help the millions of people whose health continues to be threatened by the global HIV/AIDS pandemic.

At the National Institutes of Health, the HIV/AIDS research effort is led by the National Institute of Allergy and Infectious Diseases (NIAID). A vast network of NIAID-supported scientists, located on the NIH campus in Bethesda, Maryland, and at research centers around the globe, are exploring new ways to prevent and treat HIV infection, as well as to better understand the virus with the goal of finding a cure. For example, in recent months, NIAID and its partners made progress toward finding a vaccine to prevent HIV infection. Check out other promising areas of NIAID-funded research on HIV/AIDS at http://www.niaid.nih.gov/topics/hivaids/Pages/Default.aspx .

Other NIH institutes, including the Eunice Kennedy Shriver National Institute of Child Health and Human Development and National Institute on Alcohol Abuse and Alcoholism, also support research to better control and ultimately end the HIV/AIDS pandemic. Some of these researchers have found a simple, cost-effective way to cut HIV transmission from infected mothers to their breastfed infants. Others have developed an index to help measure the role of alcohol consumption in illness and death of people with HIV/AIDS.

Find out more about these discoveries and what they mean for improving the health of people in the United States and all around the globe.

This page last reviewed on August 20, 2015

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• HIV Policy and Research
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• Reduce the Incidence of HIV
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Research Toward HIV Cure

• Address HIV-Associated Comorbidities, Coinfections, & Complications
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Viral latency and sanctuaries

Latent HIV reservoirs—small amounts of HIV that persist in people taking ART—present a significant challenge to finding a cure for HIV. Latent reservoirs remain in people with HIV when HIV becomes part of the body’s DNA in infected cells. Additionally, reservoirs of HIV can be found in certain “sanctuary” sites in the body that allow the virus to hide and be protected from both the immune system and ART. To cure HIV, the NIH supports studies to develop novel approaches and treatments that target these HIV reservoirs.

Sustained viral remission and viral eradication

Current science suggests that the path to an HIV cure involves first achieving sustained viral remission without ART. This is called sustained ART-free viral remission or a functional cure. For sustained ART-free viral remission, infectious virus must remain undetectable by sensitive testing methods for a long time without treatment. One research aim will be to prolong the time between treatments to be measured eventually not in weeks, but in months or even years. The NIH supports research into treatments leading to sustained ART-free viral remission . New cure-inducing treatments must be as safe, effective, and available for widespread use as are current-day ART regimens.

Viral eradication—eliminating the virus entirely—is the more challenging, longer-term goal.

Research Strategies

The NIH supports research to better understand how the HIV reservoir forms, persists, and reactivates, as well as investigations to develop new cure treatment strategies targeting HIV reservoirs.

A range of biomarkers and techniques, including single-cell and imaging technologies, are being studied to determine how to identify and describe the HIV reservoir. These techniques also are being used to better understand mechanisms of viral reactivation from latently infected cells.

Experimental treatments in development include therapeutic vaccines, genetically engineered immune cells that are resistant to HIV infection, drugs that reactivate latent HIV to make the virus visible to the immune system, cure-inducing immunotherapies, and interventions to permanently silence HIV in infected cells.

The search for an HIV cure involves important behavioral and social processes that complement the domains of biomedicine.  BSSR in HIV cure research is focused on important aspects such as: counseling and support interventions to address the psychosocial needs and concerns of study participants related to analytical treatment interruptions (ATIs); risk reduction in the course of ATI study participation; motivation, acceptability, and decision‐making processes of potential study participants; how cure affects the identity and social position of people with HIV; and the scalability of a proven cure strategy in the context of further advances in HIV prevention and treatment.

The NIH is leveraging resources toward an HIV cure through several public-private partnerships. NIH small business awards enable companies to help foster a diverse pipeline of experimental treatments in development. The combined support of government, industry, and nongovernmental foundations is fostering the expansion of a talented scientific workforce dedicated to advancing HIV cure research.

OAR scientist Dr. Paul Sato coordinates Research Toward an HIV Cure .

This page last reviewed on September 8, 2022

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• 28 November 2023

This is how the world finally ends the HIV/AIDS pandemic

• John Nkengasong 0 ,
• Mike Reid 1 &
• Ingrid T. Katz 2

John Nkengasong is the ambassador-at-large, US global AIDS coordinator and senior bureau official for Global Health Security and Diplomacy in the Bureau of Global Health Security and Diplomacy — PEPFAR, US Department of State, Washington DC, USA.

You can also search for this author in PubMed   Google Scholar

Mike Reid is chief science officer in the Bureau of Global Health Security and Diplomacy — PEPFAR, US Department of State, Washington DC, USA, and an associate professor at the University of California, San Francisco, USA.

Ingrid T. Katz is director for behavioural sciences in the Bureau of Global Health Security and Diplomacy — PEPFAR, US Department of State, Washington DC, USA, and an associate professor at Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts, USA.

People undergo tests for HIV at a mobile outreach clinic in the Kyenjojo District, Uganda. Credit: Jake Lyell/Alamy

You have full access to this article via your institution.

Nearly 30 years ago — more than a decade after HIV/AIDS was first identified — a group of scientists in the United States and France reported impressive results from a clinical trial. Pregnant women living with HIV could reduce the risk of transmitting the virus to their newborn child by around 67% if they took a drug called zidovudine during pregnancy and their infant took it for the first six weeks of life 1 . Five years later, a similar finding was reported in Africa 2 where, at the time, the prevalence of HIV among pregnant women exceeded 35% in several regions.

These studies, and subsequent ones that elucidated how effectively antiretroviral therapy could block parent-to-child transmission of HIV, augured an era of tremendous progress — both towards eliminating such transmission and scaling up access to life-saving treatments for children and adults living with HIV.

Since these landmark studies, 5.5 million children of mothers living with HIV have been born free of the disease . This is due in large part to a programme called the US President’s Emergency Plan for AIDS Relief (PEPFAR), created under former US president George W. Bush. Since its inception, PEPFAR, which one of us (J. N.) now leads, has ensured crucial access to life-saving treatment for more than 20 million people in at least 50 countries.

Twenty years after the programme was created, we now have the tools and knowledge to end the HIV/AIDS pandemic as a threat to public health — and to do so by 2030. According to the United Nations Programme on HIV/AIDS (UNAIDS), this would mean reaching the ‘95-95-95’ targets: at least 95% of people living with HIV should know their status; at least 95% of those people should be on life-saving antiretroviral therapy; and at least 95% of those people should have an undetectable viral load 3 . The crucial question is how do we support countries to achieve these goals?

Early efforts to combat HIV/AIDS focused on systems-level changes — the procurement of drugs, training of health workers and the provision of clinics — that were needed to ensure that effective interventions were made available to millions of people. The global health community should continue to ensure sustained investment in these systems-level strategies. But we also have an opportunity to use behavioural-science approaches to reach populations that are most in need. Making people, rather than systems, the core focus of our response is the solution to finally ending the pandemic.

Uphill battle

Botswana offers an important model for other countries (see ‘Building on success’). In 2008, 1 in 3 pregnant women aged 15–49 in Botswana were living with HIV 4 . By 2022, prevalence among women aged 15–49 had dropped to around 24% 5 , largely thanks to the government partnering with PEPFAR and other organizations, including civil society and faith-based groups. And in 2021, the World Health Organization (WHO) declared Botswana to be the first high-burden country, in which more than 2% of pregnant women are living with the virus, to be on track to eliminating new HIV infections among children .

Source: UNAIDS

Botswana’s achievements stem mainly from efforts to ensure that people living with HIV — and those at greatest risk of contracting the infection — can access life-saving interventions. These include drugs that eliminate the risk of parent-to-child transmission; antiretroviral therapy, which by suppressing the virus, both protects the infected person from severe illness and death, and blocks further transmission; condoms; voluntary male circumcision; and pre-exposure prophylaxis therapy (PrEP), all of which reduce people’s chances of contracting the virus.

But as infection becomes less common globally, it is becoming more challenging to reach the individuals and communities that continue to be severely affected by HIV/AIDS.

Hope rises that a vaccine can shield people with HIV from a deadly threat

Testing is crucial — both to link people to treatment, and to raise awareness about the possible preventive measures available to them and their partners. (Globally, an estimated 5.5 million people are living with HIV but are unaware of their status .) There is also compelling evidence that beginning antiretroviral therapy quickly — ideally on the same day as getting a diagnosis — increases the likelihood of a person taking the therapy, and of continuing to take it throughout their lives 6 .

Numerous barriers, however, prevent people — particularly those who might not be able to access care in current health-care systems — from getting tested and from receiving timely antiretroviral therapy 7 . These include anticipated or encountered stigma and discrimination, both in clinics and in the broader community; the logistical challenges of getting access to care or collecting medication; and the possibility of inciting anger and mistrust in partners or family members. Similarly, those who are most likely to benefit from various prevention strategies often feel the least empowered to access them .

No community left behind

For any one community, one strategy might work better or be more feasible at scale than another. But helping countries to achieve the 95-95-95 targets will require empowering health ministries, clinicians, community health workers and HIV activists to participate in the design of programmes that ensure everyone has access to life-long HIV care that is centred around the needs of individuals.

Most new infections occur in adolescents and young adults. So efforts should prioritize young people — specifically, girls and women aged 15–24 and men aged 25–35. Young people, aged 15–24, account for around 27% of new HIV infections globally. Yet in eastern and southern Africa — the region of the world most severely affected by HIV — only 25% of girls and 17% of boys between the ages of 15 and 19 underwent HIV testing in the past year .

Efforts should also continue to prioritize those who would benefit most from preventive treatments such as PrEP, including girls and women, sex workers and members of the LGBT+ community (people from sexual and gender minorities). These people might not be aware that they are at high risk of contracting HIV, or realize the degree to which PrEP could protect them 8 .

A youth-run HIV/AIDS centre provides counselling and testing in Bongor, Chad. Credit: Micah Albert/Redux/eyevine

Several studies over the past decade have indicated that young people, and others at greater risk of fearing and experiencing stigmatization and discrimination, benefit from having choices. They need to be able to select the combination of prevention or treatment interventions, the medication pick-up location and the frequency with which they take the drugs that work best for them 9 . But establishing youth-friendly health services can also help with this. This might entail training and supporting staff to better understand the decision-making processes, sensitivities and perspectives of young people — or providing services that are easy for young people to access while juggling school, employment, family responsibilities and so on 10 .

In a study published earlier this year, for example, researchers offered girls and women aged 18–25 information to help them with decision-making in a primary health clinic in Johannesburg, South Africa. The information package included youth-friendly information and images of various prevention interventions. The uptake of PrEP among this group was more than 90%, and after one month, twice as many people were continuing to take it, compared with the group who received standard counselling 11 .

Third patient free of HIV after receiving virus-resistant cells

Evidence-based strategies to reduce stigma are also crucial — especially for those experiencing discrimination on multiple fronts, for instance because of their age, gender, sexuality, HIV status or ethnicity. At the community and individual level, these strategies can involve using social networks to spread messages about interventions or recruiting people who have experienced their own challenges while living with HIV to talk to and motivate others. Independent monitoring of the quality of care received by those living with HIV is also key to improving services and lessening stigma and discrimination 12 .

As new prevention tools, such as the drug cabotegravir — which protects people from HIV infection for up to two months after being injected into the body — become more widely available, health-care schemes must be designed so that those who are most likely to benefit from an intervention can access it.

Changing behaviour

Whether in relation to testing, antiretroviral therapy or PrEP and other prevention interventions, incorporating behavioural and social science into the design of health-care programmes — and making this incorporation mainstream — will be essential.

A good example of the importance of behavioural interventions comes from South Africa, where men are significantly less likely than women to seek HIV testing or engage in care, and health and social-welfare systems have failed to achieve the UNAIDS 95-95-95 goals for men 13 . In 2020, researchers provided 500 men in Cape Town with a card containing information about how antiretroviral therapy can prevent an infected person from passing HIV to their partner or family and inviting them to get HIV testing at a mobile clinic. The messaging strategy almost doubled the number of men who came to the mobile clinic for free HIV testing 14 .

A meta-analysis by another group, which included data from 47 studies conducted around the world 13 , showed that leveraging social networks to improve case finding (the discovery of new cases and the determination of who is at risk) is a useful and cost-effective way to reach adolescents and youth . Leveraging social networks involves identifying certain people as being important in a social network, and then encouraging them to motivate sexual partners or those in their social networks, who might benefit from testing, to test for HIV. Partly because of the results of the meta-analysis, the WHO now recommends that countries increase their use of testing approaches that utilize social networks .

Several mutually reinforcing interventions that support people to change their behaviour can help to reduce the time between diagnosis and a person starting antiretroviral treatment. These approaches include providing people who have tested positive for HIV with text messages and other reminders to make appointments at their local clinic; ensuring that people can get to the clinic by public transport; and providing incentives, such as monetary rewards, for starting treatment 15 .

Future focus

Investing in innovative strategies that meet the needs of individuals won’t just be key to ending the HIV/AIDS pandemic by 2030. It will also help to ensure that global health systems are resilient and dynamic in the face of future public-health threats. And it will help to shift the focus of global health, so that solutions to problems for tackling disease increasingly come from the individuals and communities that are most affected, and less from high-income countries.

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Home / Innovation & Research / The innovative research behind HIV/AIDS treatment

The innovative research behind HIV/AIDS treatment

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It’s been 40 years since the release of the first scientific report describing acquired immune deficiency syndrome (AIDS). Thanks to innovative research, scientists learned how the HIV virus that causes AIDS replicates and how the immune system responds to the virus. Today, many people with HIV take just one pill a day to suppress the virus, and treatment is continuing to evolve.

In this video, Dr. Stacey Rizza , Mayo Clinic infectious disease physician and HIV researcher, explains how dedicated innovative science contributed to where we are today and what scientists are working on for the future.

What did the early research find?

Because of truly dedicated innovative science, within a few years, the scientific community figured out that AIDS was due to HIV. It then took a few years to figure out how to test for that virus. Several years later, the scientific community was able to quantitate how much virus was in a person’s blood. During all this time, truly innovative research into how the virus replicates and how the immune system responds to the virus allowed bio pharmacy companies to develop what we call anti-retroviral drugs or medications to slow down the viral replication. How has medication to treat HIV evolved?

The first drug approved for HIV was in 1987, which was AZT (now known as zidovudine). At that time, it was the fastest drug ever approved by the FDA (Food and Drug Administration) and started the fast-track mechanism through the FDA.

Then several other drugs within that same class were approved in the early 1990s. In late 1995, very early 1996, the first HIV protease inhibitors were approved. At that point, it was possible to combine three different medications from two different classes and completely suppress the HIV replication.

In the last 20 years, we’ve gone from people taking multiple medicines with lots of side effects to many of my patients with HIV now take a single pill a day. That’s a combination of medicines coformulated into one pill a day that’s extremely well-tolerated and completely suppresses their virus. We know it does not eliminate the virus. If they were to stop taking that medicine, the virus would come back. But we now have a handful of people in the world who have been what we called functionally cured of HIV, meaning they’ve gone through some research protocols that eliminated the reservoir of HIV in their body.

The new drugs are so effective in people who have fully suppressed virus that many only need to use two medications to maintain HIV treatment and control. New research is investigating ways to deliver the medications differently, such as a shot that lasts several months, or maybe someday even implantable medication delivery mechanisms so that people don’t have to take the pill every day. It is very exciting that HIV therapy is moving that direction.

Why isn’t there a cure for HIV?

The reason why it is so difficult to cure HIV is that once HIV infects a person’s body, it integrates into the host genome of several cell types. Those cells then hide in any of the lymphoid tissue, such as the lymph nodes, the liver and the spleen. And they lay there as what we call “latent” or “hiding”, as long as the person is on HIV therapy. Anytime a virus does leave a cell, it gets taken care of by HIV therapy. But if the infected individual stops the HIV therapy, that latent virus will come back. To cure HIV, you have to eliminate those hiding viruses in the cells or that latent viral reservoir, which is the term. There are many ways you can approach eliminating the reservoir.

Where is the research now?

One of the more popular ways that have been investigated is something called — and there are many different terms for it — “prime, shock, and kill” or “kick, and kill”, which is essentially giving medications that first wake the virus up from latency and then find ways to make the cells that have the virus susceptible to dying. When the virus is awake, and the cell is susceptible to dying, it kills itself but does not kill any other cells in the body.

Essentially, it specifically targets the HIV-infected cells and eliminates them without hurting anything else. This new science is exciting. It’s getting closer and closer to understanding how to do this effectively. And if you can do that with oral medications rather than fancy therapies like gene therapy or bone marrow transplant, it’s scalable to large parts of the world, and you can touch millions of people that way. That’s where the area of research is on how to make those hiding cells wake up, how to make them sensitive to die, and how to target just the HIV-infected cell.

Will we see a vaccine for HIV?

HIV has been a very hard vaccine to develop. In the world of viruses, vaccines fall into one of three buckets. They fall into the bucket where they respond to antibodies induced by the vaccine, and the vaccines are outstanding. Such viruses include polio, mumps, and lucky for us, SARS-CoV-2. Then we have the second category, like the influenza vaccine, which is about 60% effective. It certainly saves lives and makes a difference, but it’s not perfect. And then we have the third bucket, which quite frankly is the vast majority of viruses that infect humans. And HIV is in that category, where simply forming an antibody to the virus is not adequate to prevent infection. You have to do very sophisticated engineering to induce T cell effects, as well as innate effects and antibody effects. Even then, sometimes it’s very hard to decide what is the part of the virus to target. After decades, and billions of dollars of research, we’re still not there for HIV. There have been many approaches of how to do this science. Many different scientific delivery mechanisms, many different areas of the viruses targeted, many different parts of the immune system targeted, and so far, none of them have been effective at preventing HIV infection.

What needs to happen next?

We still need to slow down the number of people getting infected through good public health measures and good education to stop the HIV epidemic. We still need to get more people who are infected on therapy.

We know we can do it with public health measures. But we also need to find out more about how we eliminate that reservoir and get people cured of the virus in a simple and effective way so that we can cure more people. And the last major hurdle we have is to develop an effective vaccine. We still don’t have a vaccine that can prevent infection, a preventive vaccine, or a therapeutic vaccine where you give it to people who already have the virus that can help them control the infection. A huge amount of research has happened, but we’re still not there yet.

This article originally appeared on Mayo Clinic News Network.

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NIH Ending the HIV Epidemic Projects Bridge Gaps Between HIV Research and Public Health Practice (VIDEO)

The National Institutes of Health recently issued $26M in  awards  to HIV research institutions in its fifth year supporting implementation science under the  Ending the HIV Epidemic in the U.S.  (EHE)  initiative. These awards are the latest investments in a program that is rapidly and rigorously generating evidence to inform the unified domestic HIV response by agencies in the Department of Health and Human Services. 

The EHE initiative aims to achieve a 90% reduction in the number of new HIV infections in the United States by 2030. Since the initiative was announced in 2019, NIH has contributed by supporting implementation science projects through its network of  Centers for AIDS Research (CFAR)  and the National Institute of Mental Health (NIMH)  AIDS Research Centers (ARC) .

CFARs are co-funded by 11 NIH institutes and centers (ICs), including the National Institute of Allergy and Infectious Diseases (NIAID). NIH ICs provide scientific stewardship to participating institutions in collaboration with the  Fogarty International Center  and the  NIH Office of AIDS Research , which coordinates the NIH HIV research program across the agency. CFAR and ARC-affiliated investigators conduct research in jurisdictions that are disproportionately affected by HIV, and many of the CFAR and ARC member institutions are based in these communities.

Dr. Jeanne Marrazzo, director of the National Institute of Allergy and Infectious Diseases, describes the Ending the HIV Epidemic in the U.S. (EHE) initiative, which seeks to combat the HIV epidemic by supporting implementation science. See below:

Read how the Harvard CFAR, which is based in the high-priority jurisdiction of Suffolk County, has launched an EHE Steering Committee to support local and national EHE efforts .

• Introduction
• Conclusions
• Article Information

Figure shows mean age at HIV acquisition, mean age at HIV diagnosis, and mean time lived with diagnosed HIV in the 7 simulated HIV care scenarios. Each bar represents model-projected outcomes for a different HIV care continuum goal. The lighter portions of the bar (left) represent years spent without HIV. The yellow highlighted boxes represent time spent with undiagnosed HIV; the left border of the yellow box represents the mean age at HIV acquisition, and the right border represents the mean age at time of HIV diagnosis. The darker portions of the bars (right) represent time spent with diagnosed HIV, during which the simulated individual could be receiving or disengaged from HIV care.

We varied the HIV testing frequency (status quo testing [every 4.9 for Black men who have sex with men (MSM) and 4.6 for White MSM] and every 6 years), percentage receiving care (x-axis), and percentage virologically suppressed (y-axis) among non-Hispanic Black MSM (left, blue) and White MSM (right, gray) with HIV in the status quo care continuum. We then projected age at death with the equitable care continuum (annual HIV testing, 95% receiving HIV care, and 95% virologically suppressed) and quantified the years of life gained compared with status quo. Darker shades represent greater potential years of life gained when status quo includes less frequent HIV testing (top rows), lower receipt of care (x-axis, left), or lower virologic suppression (y-axis, bottom). The boxes in yellow represent the base case status quo national HIV care continuum.

We varied the HIV testing frequency (annually and every 6 months), percentage receiving care (x-axis), and percentage virologically suppressed (y-axis) among non-Hispanic Black men who have sex with men (MSM) (left, blue) and White MSM (right, gray) with HIV in status quo care continuum. We then projected age at death with the equitable care continuum (annual HIV testing, 95% receiving HIV care, and 95% virologically suppressed) and quantified the years of life gained compared with status quo. For scenarios in which age at death was greater than age at death under the equitable care continuum scenario, we quantified the additional years of life gained beyond the equitable care continuum. Darker shades represent greater potential years of life gained when status quo includes less frequent HIV testing (top rows), lower receipt of care (x-axis, left), or lower virologic suppression (y-axis, bottom). The solid yellow boxes represent scenarios in which years of life gained would be greater than that projected with the equitable care continuum due to more frequent HIV testing than annually. The box outlined in yellow represents the base case equitable care continuum.

eReferences

eTable 1. Comparison of Published Data and CEPAC Model Outcomes for Selected CEPAC Model Parameters of Status Quo HIV Care

eTable 2. Selected CEPAC Model Input Parameters by HIV Care Scenario

eTable 3. Comparison of Published Data and CEPAC Model Outcomes During First 5 Years From Initiation of ART for Receipt of Care and Virologic Suppression

eTable 4. Relative Mortality Ratios by Smoking and Prevalence Among Black and White People With HIV

eTable 5. Range of Smoking Prevalence Used in Sensitivity Analyses Derived From Mdodo et al

eTable 6. Current Receipt of Care and Virologic Suppression Levels Reported Among Black MSM and White MSM in Georgia, California, and New York City

eFigure 1. The HIV Care Continuum Among Non-Hispanic Black and White MSM With HIV in the US With Status Quo and Equal Improvements in Care Goals

eFigure 2. The HIV Care Continuum Among Non-Hispanic Black and White MSM With HIV in the US With Equity-Centered Goals, and Equitable Care Continuum

eFigure 3. Model Schematic

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Rich KM , Pandya A , Chiosi JJ, et al. Projected Life Expectancy Gains From Improvements in HIV Care in Black and White Men Who Have Sex With Men. JAMA Netw Open. 2023;6(11):e2344385. doi:10.1001/jamanetworkopen.2023.44385

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Projected Life Expectancy Gains From Improvements in HIV Care in Black and White Men Who Have Sex With Men

• 1 Medical Practice Evaluation Center (MPEC), Massachusetts General Hospital, Boston
• 2 Harvard Medical School, Boston, Massachusetts
• 3 Department of Health Policy and Management, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
• 4 Division of Infectious Diseases, Department of Medicine, Massachusetts General Hospital, Boston
• 5 Tobacco Research and Treatment Center, Massachusetts General Hospital, Boston
• 6 Division of Pulmonary and Critical Care Medicine, Massachusetts General Hospital, Boston
• 7 Division of General Academic Pediatrics, Massachusetts General Hospital, Boston
• 8 Department of Biostatistics, Boston University School of Public Health, Massachusetts
• 9 Orthopedic and Arthritis Center for Outcomes Research (OrACORe), Department of Orthopedic Surgery, Brigham and Women’s Hospital, Boston, Massachusetts
• 10 Policy and Innovation Evaluation in Orthopedic Treatments (PIVOT) Center, Department of Orthopedic Surgery, Brigham and Women’s Hospital, Boston, Massachusetts
• 11 Division of General Internal Medicine, Department of Medicine, Massachusetts General Hospital, Boston
• 12 Harvard University Center for AIDS Research, Harvard University, Boston, Massachusetts
• 13 Department of Medicine, Infectious Diseases, Vanderbilt University Medical Center, Nashville, Tennessee
• 14 Vanderbilt Institute for Global Health, Vanderbilt University Medical Center, Nashville, Tennessee

Question   Given existing inequities in the HIV care continuum, what are the differences in age at death between Black and White men who have sex with men (MSM) who acquire HIV, and what would be the outcome of achieving equity-centered goals?

Findings   Using a decision analytical model, the mean age at death would be 68.8 years for Black MSM and 75.6 years for White MSM given the current HIV care continuum. If HIV care is improved by equal increments for Black and White MSM, racial inequities would be the same or worsened, whereas achieving equity-centered HIV care goals would be a step toward achieving health parity between Black and White MSM.

Meaning   These findings suggest investment in equity-centered HIV care goals is critical to mitigate long-standing inequities in HIV care outcomes.

Importance   Substantial racial inequities exist across the HIV care continuum between non-Hispanic Black and White men who have sex with men (MSM) in the US.

Objectives   To project years of life gained (YLG) with improving the HIV care continuum among Black MSM and White MSM in the US and to determine the outcomes of achieving health equity goals.

Design, Setting, and Participants   The Cost-Effectiveness of Preventing AIDS Complications microsimulation model was used and populated with 2021 race-specific data to simulate HIV care among Black MSM and White MSM in the US who have acquired HIV. Analyses were completed from July 2021 to October 2023.

Intervention   The study simulated status quo care using race-specific estimates: age at infection, time to diagnosis, receipt of care, and virologic suppression. The study next projected the outcomes of attaining equity-centered vs non–equity-centered goals by simulating 2 equal improvements in care goals: (10-point increased receipt of care and 5-point increased virologic suppression), 3 equity-centered goals (annual HIV testing, 95% receiving HIV care, and 95% virologic suppression) and lastly, an equitable care continuum that achieves annual HIV testing, 95% receiving care, and 95% virologic suppression in Black MSM and White MSM. One-way and multiway sensitivity and scenario analyses were conducted.

Main Outcomes and Measures   Mean age at death and YLG.

Results   In the simulated cohort, the mean (SD) age at HIV infection was 27.0 (10.8) years for Black MSM and 35.5 (13.6) years for White MSM. In status quo, mean age at death would be 68.8 years for Black MSM and 75.6 years for White MSM. The equal improvements in care goals would result in 0.5 YLG for Black MSM and 0.5 to 0.9 YLG for White MSM. Achieving any 1 equity-centered goal would result in 0.5 to 1.7 YLG for Black MSM and 0.4 to 1.3 YLG for White MSM. With an equitable care continuum compared with the nationally reported status quo , Black MSM and White MSM would gain 3.5 and 2.1 life-years, respectively. If the status quo HIV testing was every 6 years with 75% retained in care and 75% virologically suppressed, Black MSM would gain 4.2 life-years with an equitable care continuum .

Conclusions and Relevance   In this simulation modeling study of HIV care goals, equal improvements in HIV care for Black and White MSM maintained or worsened inequities. These results suggest that equity-centered goals for the HIV care continuum are critical to mitigate long-standing inequities in HIV outcomes.

Substantial inequities persist across the HIV care continuum in the US, with Black people with HIV (PWH) bearing a disproportionate disease burden due, in part, to structural factors such as stigma, racism, and other social determinants of health. 1 - 6 Black PWH are less likely to receive prompt diagnosis, consistently receive HIV care, and achieve virologic suppression than White PWH. 2 These inequities are particularly evident between Black men who have sex with men (MSM) and White MSM. Less than 85% of Black MSM with HIV receiving care were virologically suppressed in 2021 compared with more than 90% of White MSM with HIV; virologic nonsuppression increases morbidity, mortality, and HIV transmission. 1 Reasons for these inequities are multifactorial and rooted in social and structural factors, including but not limited to legacies of slavery, mass incarceration, income inequality, and community-level stigma. 7 - 9 Inequities in access to health care have continued to persist in large part due to people being uninsured and underinsured, which disproportionately affects Black communities. 10

Reducing inequities in the HIV care continuum is 1 of the 4 key tenets of the National HIV/AIDS Strategy. 11 - 13 This initiative aligns with growing calls for local and national programs to set HIV care goals that promote health equity, or the attainment of the highest level of health for all people. 14 , 15 In contrast, goals that aim for similar increments in improvement in care across subpopulations, rather than setting identical outcome goals, allow racial inequities to persist.

To achieve health equity, investments must be made in interventions that address multilevel factors driving racial inequities, as well as evaluations of public health goals to determine effective strategies. We used simulation modeling to assess the potential implications of different HIV care continuum goals by examining which strategies would reduce gaps in life expectancy and improve outcomes among Black MSM and White MSM with HIV. Although prevention efforts, such as preexposure prophylaxis (PrEP), are essential to comprehensive care, we explicitly focused this study on improving care among MSM living with HIV to guide efforts toward strengthening the care continuum for individuals with HIV.

The Cost-Effectiveness of Preventing AIDS Complications (CEPAC) microsimulation model was used to project survival for non-Hispanic Black MSM with HIV and non-Hispanic White MSM with HIV given 7 different HIV care continuum goals. First, we populated the status quo care strategy with race-specific national estimates of testing frequency, the proportion of MSM with diagnosed HIV receiving care, and the proportion with virological suppression. We then simulated 2 equal improvements in care goals, which would attain equal absolute improvements in care between Black MSM and White MSM: (1) 10-point increased receipt of care and (2) 5-point increased virologic suppression (eFigure 1 in Supplement 1 ). We next simulated 3 equity-centered goals, in which equity between Black MSM and White MSM is achieved in 1 step of the HIV care continuum: (1) annual HIV testing for earlier diagnosis, (2) 95% receiving HIV care among MSM with diagnosed HIV, and (3) 95% virologic suppression among MSM receiving HIV care (eFigure 2 in Supplement 1 ). Last, we simulated an equitable care continuum that achieves annual HIV testing, 95% receiving HIV care, and 95% virologic suppression. 16 These goals align with recommendations from the National HIV/AIDS Strategy and the US Centers for Disease Control and Prevention (CDC). 11 , 17 , 18 To examine the association between racial inequities within the HIV care continuum and HIV care outcomes, we projected the mean age at death and compared the mean years of life gained (YLG) from attaining each HIV care continuum goal for Black MSM and White MSM with HIV.

The CEPAC model is a validated Monte Carlo microsimulation model of HIV disease and treatment. 16 , 19 - 21 Simulated individuals experience clinical events, including HIV infection, diagnosis, and virologic suppression (eAppendix and eFigure 3 in Supplement 1 ). Research projects using the CEPAC model are approved by the Mass General Brigham human research committee; we used the Consolidated Health Economic Evaluation Reporting Standards ( CHEERS ) reporting guidelines. The need for informed consent was waived in this study as no individual-level data were used. All data used in this study to create model parameters were either aggregate data from the US Centers for Disease Control and Prevention or from peer-reviewed literature.

Following infection with HIV, individuals experience a monthly decline in CD4 count while not receiving antiretroviral therapy (ART), as well as CD4-stratified risks of opportunistic infections and HIV-related mortality. HIV diagnosis is determined by a race-specific monthly probability of testing. After diagnosis, an individual can initiate ART with an integrase strand transfer inhibitor–based regimen. 22 While on ART, individuals have a rise in CD4 count and a decreased risk of opportunistic infections and other HIV-related mortality.

Higher ART adherence results in a lower risk of disengaging from care and a greater probability of virologic suppression. 23 Individuals disengaged from care have a decline in CD4 count; they also have a monthly probability of returning to HIV care. 24

HIV-related mortality depends on an individual’s CD4 count. Individuals are assigned age-specific and race-specific non–HIV-related mortality rates derived from national life tables, adjusted for smoking prevalence. 25

We populated the status quo strategy with race-specific estimates of the 2021 HIV care continuum using national data from the CDC HIV Surveillance Reports ( Table ). 1 , 26 We estimated the mean time from HIV infection until diagnosis among Black MSM and White MSM, given reported CD4 counts at diagnosis (eTable 1 in Supplement 1 ). 1 , 26 , 27 We subtracted the mean diagnostic delay from the mean age at HIV diagnosis to estimate the mean (SD) age at HIV infection: 27.0 (10.8) years for Black MSM and 35.5 (13.6) years for White MSM ( Table ). We calibrated the frequency of HIV testing among Black MSM (every 4.9 years) and White MSM (every 4.6 years) to the estimated time until HIV diagnosis. 27

We calibrated the model to achieve race-specific estimates of receipt of care and virologic suppression: 75.3% (Black MSM) and 80.3% (White MSM) with diagnosed HIV received HIV care in 2021, and 83.6% (Black MSM) and 92.4% (White MSM) receiving care were virologically suppressed (eTable 2 and eTable 3 in Supplement 1 ). 1 , 26 , 28 We defined receipt of care as documentation of 1 or more CD4 or viral load tests during 2021 and virologic suppression as a viral load level less than 200 copies/mL. 1

We derived the age-stratified monthly non–HIV-related mortality rates from non-Hispanic Black and White male US national life tables. 29 Given the higher prevalence of tobacco smoking among PWH compared with the general adult population, we adjusted these estimates for excess mortality attributable to tobacco smoking among MSM with HIV according to race-specific tobacco smoking prevalence ( Table ; eTable 4 in Supplement 1 ). 25 , 30

We conducted deterministic, 1-way sensitivity analyses to examine the outcomes of differences in age at HIV infection by simulating a cohort of Black MSM who acquire HIV at the same age as White MSM (35.5 years). We additionally performed 1-way sensitivity analyses by varying the proportion of MSM who never, formerly, and currently smoke tobacco, using reported 95% CIs of estimated smoking prevalence (eTable 5 in Supplement 1 ). 25 , 30

We examined the implications of equal improvements in care goals and equity-centered goals in 1-way scenario analyses. For equal improvements in care goals, we simulated absolute improvements in receipt of care of 5 or 15 percentage points (vs base case of 10-point increased receipt of care). In additional 1-way scenario analyses, we examined YLG with attaining equity-centered goals compared with different status quo scenarios, which reflect the wide range of current access to care among different regions and demographic groups in the US. 31 , 32 We varied the frequency of HIV testing in status quo to every 6 years and compared YLG if annual testing were attained. We next varied the status quo strategy receipt of care (75%-90%) and compared YLG attained with 95% receiving HIV care. We then varied status quo virologic suppression (75%-90%) and compared YLG with 95% virologic suppression .

Last, we conducted multiway scenario analyses to estimate YLG with attaining an equitable care continuum in regions with different status quo HIV care continuums (eTable 6 in Supplement 1 ). We varied status quo receipt of care and virologic suppression (each from 75% to 95%) at 4 status quo HIV testing frequencies: every 6 years, at base case frequency, annually, and every 6 months. We used Excel version 16.0 (Microsoft) to summarize model outcomes. Data were analyzed from July 2021 to October 2023.

We projected mean age at death to be 68.8 years among Black MSM and 75.6 years among White MSM with HIV who receive status quo HIV care, a difference of 6.8 years ( Figure 1 ). With the 10-point increased receipt of care goal, Black MSM would gain 0.5 life-years and White MSM would gain 0.9 life-years. The 5-point increased virologic suppression goal would result in 0.5 YLG for Black MSM and 0.5 YLG for White MSM. Equal improvements in care goals would maintain or worsen inequities in age at death between Black MSM and White MSM.

With the first equity-centered goal (annual HIV testing), the mean diagnostic delay would be reduced to 0.9 years for both Black MSM and White MSM. With annual HIV testing, Black MSM and White MSM would gain 0.5 life-years ( Figure 1 ). With 95% receiving HIV care, Black MSM would gain 1.7 life-years, and White MSM would gain 1.3 life-years compared with status quo . With 95% virologic suppression, Black MSM would gain 1.1 life-years, and White MSM 0.4 life-years compared with status quo. With attainment of an equitable care continuum, Black MSM would gain 3.5 life-years from status quo, whereas White MSM would gain 2.1 life-years, narrowing the gap in age at death to 5.4 years from 6.8 years.

When simulating a cohort of Black MSM who acquire HIV at a mean (SD) age of 35.5 (16.4) years, age at death would be 71.2 years (White MSM age at death, 75.6 years). When varying smoking prevalence, age at death would range between 68.4 and 69.3 years among Black MSM and between 75.6 and 76.0 years among White MSM. With varying smoking prevalence, model-projected outcomes would change by 0.1 YLG or less compared with the base case. The differences in age at death between Black MSM and White MSM were 7.2 years and 6.7 years under the scenarios of more and less prevalent smoking, respectively. If receipt of care improved by 5 to 15 percentage points in the equal improvements in care goals, Black MSM would experience 0.3 to 0.8 YLG and White MSM 0.4 to 1.3 YLG compared with status quo.

When attaining equity-centered goals with different status quo scenarios, Black MSM would gain 0.8 life-years, and White MSM would gain 0.7 life-years with attainment of the annual HIV testing goal in regions with status quo HIV testing every 6 years. When varying status quo receipt of care (from 90% to 75%), we projected that attaining 95% receiving HIV care would result in 0.5 to 1.3 YLG for Black MSM and 0.5 to 1.7 YLG for White MSM. When varying status quo virologic suppression (from 90% to 75%), we projected that achieving 95% virologic suppression would result in 0.3 to 1.7 YLG for Black MSM and 0.3 to 1.5 YLG for White MSM.

We projected YLG if an equitable care continuum was attained compared with different status quo HIV care continuums. In regions with infrequent HIV testing (every 6 years), projected outcomes with an equitable care continuum would result in 0.7 to 4.2 YLG for Black MSM and 0.5 to 4.0 YLG for White MSM if status quo receipt of care and virologic suppression were both 95% or 75%, respectively ( Figure 2 ). An equitable care continuum would result in 0.6 to 4.0 YLG for Black MSM and 0.5 to 3.7 YLG for White MSM in regions with status quo HIV testing frequency (Black MSM, every 4.9 years; White MSM, every 4.6 years), and receipt of care and virologic suppression were both 95% or 75%, respectively ( Figure 2 ). In regions with annual HIV testing in status quo but 75% receiving care and 75% virologically suppressed, attaining an equitable care continuum would result in up to 3.4 YLG for Black MSM and 3.2 YLG for White MSM ( Figure 3 ). Further improvements in care (HIV testing every 6 months, 95% receiving HIV care, and 95% virologic suppression) would result in an additional 0.2 YLG (Black MSM) and 0.3 YLG (White MSM) compared with an equitable care continuum and annual HIV testing ( Figure 3 ).

We assessed existing inequities across the HIV care continuum and projected the potential outcomes of attaining different goals in the HIV care continuum to address racial inequities, using a decision analytical model. We projected a 6.8-year difference in age at death between Black MSM and White MSM with HIV in the US, according to the current HIV care continuum. Attaining equal improvements in care goals would maintain or worsen existing inequities. In contrast, the equity-centered goal of 95% virologic suppression would result in 0.7 more life-years gained for Black MSM compared with White MSM and thus reduce but not eliminate existing inequities. The greatest potential benefits would occur with an equitable care continuum, particularly among Black MSM, who would gain 3.5 life-years. These model-based results emphasize how an equity-centered approach across the HIV care continuum is critical to improve care outcomes and reduce racial inequities in HIV care.

When examining scenarios that focus on individual steps in the care continuum, we found that improving receipt of care would result in more years of life gained than achieving national goals for improving HIV testing or virologic suppression. These findings are likely due to the larger gap between current and goal levels of receiving HIV care compared with testing and virologic suppression. Additionally, synergies exist in the HIV care continuum; more people can attain virologic suppression if more people receive HIV care.

Although interventions to increase receipt of HIV care will improve clinical outcomes, our findings highlight that a combination of equity-centered strategies is critical. A combination of more frequent HIV testing, improved receipt of care, and increased virologic suppression would result in at least twice the gain in life-years than would occur with achieving an improvement goal in any 1 of the care continuum steps.

To achieve an equitable care continuum, there is a need for investment in and prioritization of evidence-based, multilevel interventions developed to meet the needs of Black MSM in different community contexts and that consider local HIV epidemic dynamics. 33 - 36 For example, it is essential to address structural issues due to health care infrastructure (eg, dearth of HIV practitioners, lack of Medicaid expansion, and medical mistrust) that are associated with a higher burden of HIV in the US South and to develop tailored interventions focused on the community and cultural context for Black MSM residing in the US South. Such interventions are also likely to provide benefits to the community at large by reducing forward transmission of HIV (eg, treatment as prevention) among other benefits. 3 , 37

The importance of equity-centered initiatives, with explicit, longitudinal engagement of disproportionately affected communities, has been recognized at both the local and federal level. 38 , 39 For example, the National Institutes of Health have funded the E2i Initiative 5 , 38 , 40 , 41 to develop and more rapidly scale-up interventions among key populations, such as Black MSM. One example is the Health Models Program, 42 which provided financial incentives, counseling, and patient navigation services to Black MSM with HIV at a total mean cost of $161/person during the 3-year study. Another program has formed close partnerships with Black-owned barbershops to increase access to health information, with the goal of decreasing HIV stigma and increasing linkage and engagement in care. 43 Recent advances in treatment, particularly long-acting injectable ART formulations, also hold promise to improve virologic suppression but must be implemented using care models that ensure needed access to priority populations despite structural barriers. 23 , 44 Most published interventions that focus on improving HIV care continuum outcomes for Black MSM have been individual-level interventions focused on medication adherence; structural interventions that further address multiple steps in the care continuum are needed. 3 , 5

Even with attainment of an equitable care continuum, this modeling analysis projects that Black MSM with HIV would still die at a younger age than White MSM with HIV. This finding is in part, but not entirely, due to the earlier mean age at which Black MSM acquire HIV than White MSM. Improving uptake of HIV prevention strategies, such as PrEP, is of critical importance to ending the HIV epidemic and reducing inequities, and equity-centered interventions must also include prevention services for people without HIV, including equitable access to PrEP and harm reduction services. 45 The gap in life expectancy is also likely due to inequities in non–HIV-related mortality. Black men experience higher rates of chronic health conditions than White men. 46 - 48 Social and structural barriers drive these health inequities, including unequal access to health care, income and housing inequality, and multilevel stigma, all of which contribute to both HIV-related and non–HIV-related health risks. 7 , 8

Our study adds to a growing body of studies that estimate the potential benefits of specific initiatives on inequities along the HIV care continuum. 14 A recent modeling analysis found that focusing HIV prevention and treatment service distribution to match the racial and ethnic proportion of new HIV diagnoses in 6 US cities would result in greater gains of quality–adjusted life-years than if services were scaled up by an equal absolute amount across racial and ethnic groups. 49 This study used distributional cost-effectiveness analysis, which provides a methodological framework to assess specific strategies projected to worsen (or reduce) disparities in outcomes between groups when also considering cost. 50 We recommend that future cost-effectiveness analyses include distributional cost-effectiveness analysis methods to expand the evidence base for strategies that would reduce racial inequities.

There are several limitations to this analysis. Model-projected outcomes are affected by data uncertainty, which we examined with sensitivity and scenario analyses. 51 Because this analysis focused on individual outcomes for people with HIV, we did not include HIV transmissions or PrEP, which are crucial components in multifaceted strategies to decrease transmissions and end the HIV epidemic. 52 , 53 Black MSM and White MSM were the focus of this analysis; further analysis is needed to assess implications for MSM who identify as Hispanic and/or Alaskan Native and Indigenous American, as well as other communities who experience high barriers to care, including women with HIV. This study quantified inequities in age at death and the potential years of life gained if HIV care goals were met; further knowledge of the specific drivers of inequities is needed to develop effective, evidence-based strategies to reduce inequities.

Equity-centered solutions across the HIV care continuum are critical to mitigate inequities in care among MSM with HIV in the US. Increasing receipt of care and virologic suppression using equity-centered goals would result in more years of life gained for Black MSM compared with White MSM in the US, given the current status quo; this would begin to bring life expectancy among Black MSM closer to parity with White MSM. Our results suggest that equity-centered approaches could be a successful strategy to improve HIV care for MSM. Allocating resources to develop and identify effective equity-centered, evidence-based interventions for Black MSM and implementation strategies to deploy these interventions will be essential to achieve health equity across the HIV care continuum.

Accepted for Publication: October 12, 2023.

Published: November 28, 2023. doi:10.1001/jamanetworkopen.2023.44385

Open Access: This is an open access article distributed under the terms of the CC-BY License . © 2023 Rich KM et al. JAMA Network Open .

Corresponding Author: Emily P. Hyle, MD, MSc, Division of Infectious Diseases, Massachusetts General Hospital, 100 Cambridge St, 16th Floor, Boston, MA 02114 ( [email protected] ).

Author Contributions: Dr Rich had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Ahonkhai and Hyle contributed equally to this work as co-senior authors.

Concept and design: Rich, Pandya, Ciaranello, Losina, Ahonkhai, Hyle.

Acquisition, analysis, or interpretation of data: Rich, Chiosi, Reddy, Shebl, Ciaranello, Neilan, Pinkney, Losina, Freedberg, Ahonkhai, Hyle.

Drafting of the manuscript: Rich, Ahonkhai, Hyle.

Critical review of the manuscript for important intellectual content: All authors.

Statistical analysis: Rich, Pandya, Shebl, Losina.

Obtained funding: Rich, Freedberg, Hyle.

Administrative, technical, or material support: Chiosi, Reddy, Ciaranello.

Supervision: Reddy, Freedberg, Hyle.

Conflict of Interest Disclosures: Dr Chiosi reported receiving grants from the National Institutes of Health (NIH) outside the submitted work. Dr Reddy reported receiving grants from the NIH during the conduct of the study and royalties from UpToDate, Inc outside the submitted work. Dr Ciaranello reported receiving grants from the NIH during the conduct of the study. Dr Neilan reported receiving grants from the NIH during the conduct of the study. Dr Losina reported receiving grants from Brigham and Women’s Hospital during the conduct of the study. Dr Freedberg reported receiving grants from the NIH during the conduct of the study. Dr Ahonkhai reported receiving personal fees from ViiV, Vindico HIV Management Special Populations CME, Gilead, and Integritas HIV Management Special Populations CME outside the submitted work. Dr Hyle reported receiving grants from the NIH and Masschusetts General Hospital during the conduct of the study, being a member of the Department of Health and Human Services Panel on Antiretroviral Guidelines for Adults and Adolescents, and being coauthor of articles on UpToDate.com. No other disclosures were reported.

Funding/Support: This publication was made possible by funding from the US NIH (R01 AG069575 [to Dr Hyle], R01 AI042006 [to Dr Freedberg], R01 DA050482 [to Dr Reddy], T32 AI007433 [to Pinkney], R25 MH119857 [to Dr Pinkney], K08 HD094638 [to Dr Neilan], and P30 AI110527 [to Dr Ahonkhai]), the Jerome and Celia Reich Endowed Scholar Award (to Dr Hyle), the Infectious Diseases Society of America/HIV Medicine Association Grants for Emerging Researchers/Clinicians Mentorship Program Award (to Dr Rich), the Steve and Deborah Gorlin Massachusetts General Hospital Research Scholar Awards (to Dr Freedberg), the Massachusetts General Hospital Scholar Award in Population and Health Care Research (to Dr Ciaranello), the Massachusetts General Hospital Executive Committee on Research Fund for Medical Discovery (to Dr Chiosi), and the Doris Duke Foundation Physicians Scientist Fellowship (to Dr Chiosi).

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Disclaimer: The contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH or other funders.

Data Sharing Statement: See Supplement 2 .

Additional Contributions: We appreciate Mr Munashe Machoko, BA, and Ms Julie Deleger, BA (Medical Practice Evaluation Center, Department of Medicine, Massachusetts General Hospital, Boston), for their assistance with manuscript preparation. Neither were compensated for their efforts beyond their normal salary.

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PACHA Members Discuss HIV Research Highlights from CROI 2024 By HIV.gov

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Each year, the Conference on Retroviruses and Opportunistic Infections (CROI) features an array of exciting new developments in HIV research that can help support the health and well-being of people across the globe. Before the start of the 80 th full council meeting of the Presidential Advisory Council on HIV/AIDS (PACHA) in Houston, TX, HIV.gov had the opportunity to speak with PACHA members Patrick Sullivan, DrPH, MPH, Professor of Epidemiology at Emory University’s Rollins School of Public Health, and Jeff Taylor, Executive Director of the HIV and Aging Research Project, who both attended CROI 2024, about what they presented and what stood out to them at this year’s conference. Watch their conversation Exit Disclaimer :

Mentorship and HIV and Aging Research

Mr. Taylor noted that this year was the first time a formal mentorship program for advocates was launched at the conference, with seasoned mentors paired with new Community Educator Scholars to support and engage them to ensure they got the most out of CROI. He also reflected on the range of research presented at CROI related to HIV and aging. He noted that there continue to be findings presented via abstracts and presentations from the NIH-supported  REPRIEVE trial , a global study that demonstrated that a statin, a cholesterol-lowering medication, may offset the high risk of cardiovascular disease in people with HIV by more than a third, potentially preventing one in five major cardiovascular events (e.g., heart attacks, strokes, or surgery to open a blocked artery) or premature deaths in this population. As he noted,  new clinical guidelines were recently published based on those findings, helping clinicians better support the health of those ages 40-75. ( View HIV.gov’s CROI 2024 conversation with Dr. Carl Dieffenbach about new REPRIEVE trial findings .)

The Further Promise of PrEP

Dr. Sullivan discussed new evidence from a study he and his colleagues at Emory University conducted Exit Disclaimer showing that, over the past decade, U.S. states with high PrEP coverage among those who need it experienced steeper declines in new HIV diagnoses rates than states with low PrEP coverage. Their analysis showed that from 2012 to 2021, states with the lowest levels of PrEP coverage saw an annual increase in new HIV diagnoses, while all other states saw an annual decrease in HIV diagnoses, with the largest decreases among states with the highest levels of PrEP coverage. In other words, he emphasized, while we’ve known for decades that PrEP works to prevent HIV at the individual level, we now know that when we remove barriers to PrEP access and take PrEP to scale, we can see an impact on the population level as well. He further noted that other studies presented at CROI 2024 about all stages in the PrEP cascade—awareness, access, uptake, and adherence—show that we have the tools to get us to that high level of PrEP coverage and better knowledge of how to deploy them.

Catch Up on Other CROI HIV Research Updates

Mr. Taylor also shared an important observation about the opening session with the HIV.gov team as we were working on this blog. He noted, “There was ongoing discussion at CROI regarding stigma as an obstacle to ending the epidemic. Ugandan activist Frank Mugisha, Sexual Minorities Uganda (SMUG), highlighted the chilling impact of new laws criminalizing LGBTQ individuals during the conference's opening plenary. He added that these laws hinder access to HIV care and threaten progress against HIV and that discriminatory policies can cripple the fight against HIV.”

HIV.gov has shared other interviews from CROI 2024 with federal HIV leaders, participating researchers, and community members. You can find all of them on HIV.gov’s social media channels and with recaps here on the blog available by using the CROI topic tag .

More than 3,600 HIV and infectious disease researchers from 73 countries gathered in Denver and virtually from March 3-6 this year for CROI, an annual scientific meeting on the latest research that can help accelerate global progress in the response to HIV and other infectious diseases, including STIs and viral hepatitis. Over 1,000 summaries of original research were presented. Visit the conference website Exit Disclaimer for more information. Session webcasts and more information will be published there for public access in 30 days.

Related HIV.gov Blogs

• Aging Aging and HIV
• CROI Conference on Retroviruses & Opportunistic Infections
• PACHA Presidential Advisory Council on HIV/AIDS
• PrEP Pre-Exposure Prophylaxis

Small protein plays big role in chronic HIV infection

UC Riverside-led study on innate immune system may lead to new treatments for patients with neuroHIV

NeuroHIV refers to the effects of HIV infection on the brain or central nervous system and, to some extent, the spinal cord and peripheral nervous system. A collection of diseases, including neuropathy and dementia, neuroHIV can cause problems with memory and thinking and compromise our ability to live a normal life. 

Using a mouse model of neuroHIV, a research team led by biomedical scientists at the University of California, Riverside, studied the effects of interferon-β (IFNβ), a small protein involved in cell signaling and integral to the body’s natural defense mechanism against viral infections. The researchers found that higher or lower than normal levels of IFNβ affect the brain in a sex-dependent fashion: some changes only occur in females, others only in males.

Marcus Kaul , a professor of biomedical sciences in the School of Medicine who led the study , explained that when infection-induced IFNβ levels become high, the brains of females and males are protected. If IFNβ production in response to infection is absent or too low, HIV can compromise brain function right away in both females and males, he said. 

“However, IFNβ also controls other cell and brain functions,” Kaul said. “If IFNβ is absent, females display reduced nerve cell connections called dendrites in the cerebral cortex, while males show diminished ‘presynaptic terminals,’ another type of nerve cell connection, in the hippocampus.” 

Dendrites are highly branched structures that increase the receptive surface of neurons. 

“Paradoxically, in the hippocampus of females and males, the damage to presynaptic terminals by HIV is diminished when IFNβ is absent but the reduction of injury is more pronounced in males,” Kaul said.

According to the researchers, the work adds to scientists’ understanding of how innate immunity affects the brain during chronic HIV infection.

“Until now, it was not known that normal levels of IFNβ are required for normal memory function and that the absence of IFNβ changes the production of nerve cell components in a sex-dependent fashion,” Kaul said. 

The findings, published in the journal Brain, Behavior, and Immunity , are noteworthy because the mouse model of neuroHIV that Kaul and his team used shares key features of brain injury and compromised function, such as impaired memory, with people living with HIV infection, or PLWH. 

Almost all cells in the body can produce IFNβ. Kaul explained IFNβ regulates the production of inflammatory factors in neuroHIV and has two major effects: (a) it changes the state of a virally infected cell from ‘normal’ to ‘anti-viral,’ making the cells uncomfortable environments for the virus, even completely shutting down virus production, and (b) IFNβ is released from infected cells as well as specialized cells that, by sensing infected cells, can alert neighboring cells and the entire body of a viral infection. 

“This is how neighboring cells adapt to become more resistant to viral infection,” Kaul said. “Some of them will also release additional anti-viral factors and a mixture of other factors that can promote or limit inflammation, such as cytokines called CCL3, CCL4 and CCL5.”   

The research was performed in Kaul’s laboratory. The team generated a new variant of an established transgenic mouse model of neuroHIV by crossbreeding this model with mice that lack IFNβ. The team then analyzed memory function and brain tissue of the transgenic mice for injury that usually occurs in neuroHIV.

“HIV and some other viruses have developed mechanisms to reduce or even prevent the production of more than normal levels of IFNβ,” said Hina Singh , an assistant project scientist in Kaul’s lab and the first author of the research paper. “We know little about the role of IFNβ in the human brain beyond that it can reduce inflammation. This is a major reason why IFNβ is used to treat multiple sclerosis, an autoimmune disease that affects more than 2.8 million people worldwide . Currently, we have almost no information about how much IFNβ is present in the brains of PLWH and what it does there.”

Singh said the study underscores the importance of having normal levels of IFNβ during no viral infection and having sufficiently high levels of IFNβ in case of neuroHIV or other viral infections. 

“The body’s many anti-viral responses observed in HIV infection are not specific to HIV but also occur with other viral infections,” she said. “But in contrast to most other viral infections, the body cannot get rid of HIV, which diminishes the effectiveness of the natural IFNβ response.”

Next, the team plans to work on confirming the findings of the neuroHIV model in PLWH. 

“For this, we will need to investigate tissues of PLWH who consented to donate them for research after death,” Kaul said. “Ultimately, we hope to develop IFNβ into a therapy for patients with neuroHIV.”

The study was funded by grants to Kaul from the National Institutes of Health. Kaul and Singh were joined in the research by scientists at UCR and The Scripps Research Institute in La Jolla, California.

The title of the research paper is “Interferon-β deficiency alters brain response to chronic HIV-1 envelope protein exposure in a transgenic model of NeuroHIV.” The paper is scheduled to appear in print in May 2024.

Second related study

Another study from the Kaul lab is scheduled to appear in print in the May 2024 issue of Brain, Behavior, and Immunity. 

“This study adds another important aspect to our understanding of how innate immunity and an inflammatory mechanism affects the brain during chronic HIV infection,” Kaul said.

The study shows that intact HIV and its viral envelope protein gp120 each cause macrophages, a type of white blood cell, to release cysteinyl leukotrienes, or CysLTs, which are pro-inflammatory mediators. The study shows for the first time that the CysLTs are critical components of macrophage neurotoxicity induced by HIV-1 , the most common of the two major types of HIV. 

“The potential translational value of our work is the demonstration that an asthma drug approved by the Food and Drug Administration, that inhibits a major receptor for CysLTs also prevents HIV-induced neurotoxicity,” Kaul said.

The research paper is titled “A critical role for Macrophage-derived Cysteinyl-Leukotrienes in HIV-1 induced neuronal injury.” Nina Yuan, a former associate specialist researcher in the Kaul lab, is the paper’s lead author. This study was supported by funds from the National Institute of Health.

Header photo shows Hina Singh (left) and Marcus Kaul. (UCR/Kaul lab)

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Gene Editing Breakthrough: CRISPR-Cas9 Successfully Excises HIV from T-cells in Major Research Leap

T he CRISPR-Cas9 genome editing tool has demonstrated the capability to eradicate HIV viruses from cells cultured in laboratory settings, as per preliminary research slated for presentation at this year’s European Congress of Clinical Microbiology and Infectious Diseases (ECCMID) in Barcelona.

While emphasizing that these findings are currently in the “proof-of-concept” stage and are distant from potential clinical application, the research represents a significant advancement that could potentially advance the pursuit of an HIV cure.

The recipients of the 2020 Nobel Prize in Chemistry were recognized for their pioneering work in uncovering the CRISPR-Cas9 genome editing system.

Functioning akin to molecular scissors, this editing tool precisely excises and alters segments of an organism’s genetic sequence. Its applications encompass a range of uses, including the removal of undesirable or defective genes and the insertion of fresh genetic material in their stead.

Progress in CRISPR-based therapies is already underway, with the inaugural treatment receiving approval from the US Food and Drug Administration (FDA) in 2023 for the management of sickle cell disease.

The researchers, whose findings are slated for presentation at ECCMID, harnessed this technology to target HIV, a virus known to infect immune cells such as T cells, macrophages, and dendritic cells.

Currently, HIV infection is manageable with lifelong antiviral therapy, which reduces the viral load to undetectable levels but does not offer a cure. This is primarily attributed to the virus’s ability to integrate its genetic material into the host’s DNA, rendering it challenging to eradicate. Moreover, discontinuation of antiviral treatment can lead to HIV rebounding from reservoirs of other infected cells.

In a press release, the researchers articulated their goal of developing a robust and safe combinatorial CRISPR-Cas regimen aimed at achieving an inclusive “HIV cure for all.” Their objective is to deactivate diverse strains of HIV across various cellular contexts.

The researchers pursued a comprehensive strategy by employing CRISPR to target two regions of the HIV genome that exhibit conservation across all identified strains of the virus. Yet, they encountered a challenge when they discovered that the size of the vehicle carrying the CRISPR-Cas9 reagents to the infected cells was too large. Consequently, they needed to reduce the size of the vehicle to facilitate easier transportation.

Relevant articles:

– CRISPR Gene Editing Eliminates HIV From Infected Cells

– Gene Editing Can Eliminate HIV From Cell Culture, Researchers Claim , Technology Networks, Sat, 23 Mar 2024 07:00:00 GMT

– Preclinical safety and biodistribution of CRISPR targeting SIV in non-human primates , Nature.com, Thu, 17 Aug 2023 07:00:00 GMT

– CRISPR gene therapy appears safe, but claims of an imminent HIV cure are premature , aidsmap, Fri, 03 Nov 2023 07:00:00 GMT

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HIV/AIDS epidemiology, pathogenesis, prevention, and treatment

The HIV-1 pandemic is a complex mix of diverse epidemics within and between countries and regions of the world, and is undoubtedly the defining public-health crisis of our time. Research has deepened our understanding of how the virus replicates, manipulates, and hides in an infected person. Although our understanding of pathogenesis and transmission dynamics has become more nuanced and prevention options have expanded, a cure or protective vaccine remains elusive. Antiretroviral treatment has transformed AIDS from an inevitably fatal condition to a chronic, manageable disease in some settings. This transformation has yet to be realised in those parts of the world that continue to bear a disproportionate burden of new HIV-1 infections and are most a% ected by increasing morbidity and mortality. This Seminar provides an update on epidemiology, pathogenesis, treatment, and prevention interventions pertinent to HIV-1.

HIV pandemic

An estimated 38·6 (33·4–46·0) million people live with HIV-1 worldwide, while about 25 million have died already. 1 In 2005 alone, there were 4·1 million new HIV-1 infections and 2·8 million AIDS deaths. 1 These estimates mask the dynamic nature of this evolving epidemic in relation to temporal changes, geographic distribution, magnitude, viral diversity, and mode of transmission. Today, there is no region of the world untouched by this pandemic ( figure 1 ). 2

HSex=heterosexual. MSM=Men who have sex with men. IDU=injection drug users. Based on Joint UNAIDS and WHO AIDS epidemic update December, 2005.

Heterosexual transmission remains the dominant mode of transmission and accounts for about 85% of all HIV-1 infections. Southern Africa remains the epicentre of the pandemic and continues to have high rates of new HIV-1 infections. 3 Although overall HIV-1 prevalence remains low in the emerging epidemics in China and India, the absolute numbers, which are fast approaching those seen in southern Africa, are of concern. 1 Outside of sub-Saharan Africa, a third of all HIV-1 infections are acquired through injecting drug use, most (an estimated 8·8 million) of which are in eastern Europe and central and southeast Asia. 1 The rapid spread of HIV-1 in these regions through injecting drug use is of importance, since it is a bridge for rapid establishment of more generalised epidemics.

A defining feature of the pandemic in the current decade is the increasing burden of HIV-1 infections in women, 4 which has additional implications for mother-to-child transmission. Women now make up about 42% of those infected worldwide; over 70% of whom live in sub-Saharan Africa. 1 Overall, a quarter of all new HIV-1 infections are in adults aged younger than 25 years. 1 HIV-1 infection rates are three to six times higher in female adolescents than in their male counterparts, 1 , 5 – 7 and this difference is attributed to sexual coupling patterns of young women with older men. Population prevalence of HIV-1 infection, concurrent sexual relationships, partner change, sexual practices, the presence of other sexually transmitted diseases, 8 – 11 and population mobility patterns 12 – 14 for economic and other reasons (eg, natural disasters and wars) further increase the probability of HIV-1 acquisition. 3 , 15 Emerging data accord with strong links between risk of sexual HIV-1 acquisition and episodic recreational drug or alcohol use. 16

Although sub-Saharan Africa continues to bear a disproportionate burden of HIV-1 infections, there is now an increasing number of countries reporting stabilisation or declines in prevalence (eg, Zambia, Tanzania, Kenya, Ghana, Rwanda, Burkina Faso, and Zimbabwe). 1 There is some evidence to attribute these reductions to effective changes in sexual behaviour, such as postponement of sexual debut, reduction in casual relationships, and more consistent condom use in casual relationships. 17 , 18 However, increasing morbidity and mortality rates associated with a maturing HIV-1 epidemic need to be considered when interpreting these data. 19 For example, the death of a few high-risk individuals who are key to transmission chains could exert a major effect on sexual networks and result in major reductions in infection rates. 20 Additionally, since most HIV-1 estimates are based on surveys in antenatal populations, increasing morbidity and mortality could cause the numbers of women in this group to decrease, and thus lead to underestimates of the true prevalence in these countries. 19

Although the relative contribution of cell-free virus compared with cell-associated virus in HIV-1 transmission remains unclear, there is growing evidence that viral load is predictive of transmission risk. 21 , 22 The highest levels of viraemia are seen during acute infection and advanced HIV-1 disease. 22 Further, co-infections with other sexually transmitted diseases in asymptomatic HIV-1 infected people can increase viral shedding to levels similar to those seen during acute infection. 23 Thus, sexually transmitted diseases could enhance HIV-1 transmission to rates similar to those seen during primary infection. 24 This observation could help to explain why the efficiency of HIV-1 transmission exceeds, in some settings, the earlier mathematical projections. 25 Thus, identification and treatment of recently infected people is an important means to reduce transmission. However, most people are unaware of their HIV-1 status during these crucial first months of infection. Several screening strategies based on laboratory testing and clinical algorithms are being developed and tested 26 for efficient identification of early infection before antibody development. 27 Additionally, a more aggressive management of sexually transmitted infections in settings with generalised epidemics has the potential to affect current epidemic trajectories. 24

Based on their genetic make-up, HIV-1 viruses are divided into three groups (eg, M [main], N, and O group, figure 2 ). These HIV-1 groups and HIV-2 probably result from distinct cross-species transmission events. 28 Pandemic HIV-1 has diversified into at least nine subtypes ( figures 1 and ​ and2) 2 ) and many circulating recombinant forms, 29 , 30 which encode genetic structures from two or more subtypes (eg, A/E=CRF01; A/G=CRF02). The continuously evolving HIV-1 viral diversity poses an immense challenge to the development of any preventive or therapeutic intervention. 29

The HIV-1 pandemic is largely due to viral isolates belonging to the HIV-1 M-group, with HIV-1 subtype C being the most prevalent (red). Recombinant circulating forms cluster with the M-group but have been omitted for clarity. HIV-1 M group and the contemporary SIV strains identified in wild chimpanzees in Cameroon (SIVcpzLB7/EK5 28 ) are highlighted. HIV-1 sequences cluster closely with SIV from chimpanzees (SIVcpz), whereas HIV-2 resembles SIV from macaques and sooty mangabeys (SIVmac/SIVsm).

In terms of viral diversity, subtype C viruses continue to dominate and account for 55–60% of all HIV-1 infections worldwide ( figure 1 ). 30 Non-subtype B isolates might differ in their virological characteristics from the subtype B isolates (eg, viral load, chemokine co-receptor usage, transcriptional activation in specific biological compartments). 31 – 33 However, the clinical consequences of subtype variations remain unclear.

Infection with two or more genetically distinct viruses could lead to new recombinant viruses. Recombination takes place at a higher rate than initially predicted, 30 and circulating recombinant forms account for as much as 20% of infections in some regions (eg, southeast Asia). 31 These findings are in agreement with the occurrence of co-infections with multiple distinct isolates in a close temporal context. 34 – 36 Further, superinfections in which time points of virus acquisition are months to years apart have been described, although at a much lower frequency than co-infections. 34 , 37 – 39 Collectively, these observations challenge the assumption that HIV-1 acquisition happens only once with a singular viral strain and that, thereafter, the infected individual is protected from subsequent infections. 40 This lack of immunisation has substantial implications for vaccine development. Emerging evidence suggests that clinical progression to AIDS might be more rapid in individuals with dual infections, 35 and encouraging safer sex practices in viraemic HIV-1-infected people might be appropriate to keep recurrent exposure to new viral strains to a minimum.

Pathogenesis of HIV-1

The worldwide spread of HIV-1 indicates that the virus effectively counteracts innate, adapted, and intrinsic immunity. 41 , 42 Despite its modest genome size (less than 10 kb) and its few genes ( figure 3 ), HIV-1 excels in taking advantage of cellular pathways while neutralising and hiding from the different components of the immune system. 43 – 45 Notably, our understanding of pathogenesis is often derived from studies of subtype B viruses and non-human primate studies.

(A) Envelope glycoproteins gp120/41 form the spikes on the virion’s surface. During maturation the gag protein is cleaved and Gag p24 forms the core. The viral genome, viral reverse transcriptase (RT), integrase as well as a number of host proteins are encapsidated. (B) Dir erent steps of the viral life cycle on a cellular level and the potential targets for treatment interventions. (C) HIV-1 has evolved strategies to counteract the restriction factors TRIM5α and APOBEC3G/3F. If left unchecked by HIV-1 Vif, APOBEC3G/3F is encapsidated into the egressing virion, and on infection of a target cell leads to G-to-A hypermutations in the viral genome. Rhesus TRIM5α inhibits HIV-1 replication early after infection of the target cell before the step of reverse transcription.

The HIV-1 life cycle is complex ( figure 3 ) and its duration and outcome is dependent on target cell type and cell activation. 46 In the early steps, HIV-1 gains access to cells without causing immediate lethal damages but the entry process can stimulate intracellular signal cascades, which in turn might facilitate viral replication. 47 , 48 The two molecules on the HIV-1 envelope, the external glycoprotein (gp120) and the transmembrane protein (gp41), form the spikes on the virion’s surface. 49 During the entry process, gp120 attaches to the cell membrane by first binding to the CD4+ receptor. Subsequent interactions between virus and chemokine co-receptors (eg, CCR5, CXCR4) trigger irreversible conformational changes. 49 , 50 The actual fusion event takes place within minutes by pore formation, 50 , 51 and releases the viral core into the cell cytoplasm. After the core disassembles, the viral genome is reverse transcribed into DNA by the virus’ own reverse transcriptase enzyme. 46 Related yet distinct viral variants can be generated during this process since reverse transcriptase is error prone and has no proofreading activity. 46 At the midpoint of infection, the viral protein integrase in conjunction with host DNA repair enzymes inserts the viral genome into gene-rich, transcriptionally active domains of the host’s chromosomal DNA. 52 – 54 An integrase binding host factor, LEDGF/p75 (lens epithelium-derived growth factor), facilitates integration, 55 , 56 which marks the turning point by irreversibly transforming the cell into a potential virus producer. In the late steps, production of viral particles needs host driven as well as virus driven transcription. 46 Viral proteins are transported to and assemble in proximity to the cell membrane. Virus egress from the cell is not lytic and takes advantage of the vesicular sorting pathway (ESCRT-I, II, III), which normally mediates the budding of endosomes into multivesicular bodies. 57 , 58 HIV-1 accesses this protein-sorting pathway by binding TSG101 via its late domain, a short sequence motif in p6 of Gag. 59 , 60 Cleavage of the Gag-Pol poly-protein by the viral protease produces mature infectious virions. 46 , 61

Since cytoplasmic molecules of the producer cell and components from its cell surface lipid bilayer are incorporated into the new viral particle, virions bear characteristics of the cells in which they were produced. 62 Incorporated host molecules can determine the virus’ phenotype in diverse ways (eg, shape the replicative features in the next cycle of infection or mediate immune activation of bystander cells 62 ).

Studies of the early events that happen after HIV-1 breaches the mucosal barrier suggest the existence of a window period in which viral propagation is not yet established and host defences could potentially control viral expansion. 63 The important co-receptors for HIV-1 infection are two chemokine receptors—CCR5 and CXCR4. Independently of the transmission route, most new infections are established by viral variants that rely on CCR5 usage. 64 CXCR4-tropic viruses generally appear in late stages of infection and have been associated with increased pathogenicity and disease progression. 65

Compelling evidence from non-human primate models (eg, simian immunodeficiency virus [SIV] infection of rhesus macaques) suggest that vaginal transmission results in infection of a small number of CD4+ T lymphocytes, macrophages, and dendritic cells located in the lamina propria. 63 Potential pathways for virus transmission involve endocytosis, transcytosis, and virus attachment to mannose C-type lectin receptors (eg, DC-SIGN) located on dendritic cells and macrophages. 66 The initial replication takes place in the regional lymph organs (eg, draining lymph nodes) and is composed of few viral variants, and leads to modest primary amplification. With migration of infected T lymphocytes or virions into the bloodstream, secondary amplification in the gastrointestinal tract, spleen, and bone marrow results in massive infection of susceptible cells. In close temporal relation with the resulting peak of viraemia (eg, 10 6 to 10 7 copies per mL plasma), clinical symptoms can be manifest during primary HIV-1 infection ( figure 4 ). The level of viraemia characteristic for the chronic phase of infection in an individual (viral set point) differs from the peak viraemia by one or two orders of magnitude. This reduction is largely attributed to HIV-1 specific CD8+ responses but target cell limitation could also play a part. The viral population is most homogeneous early after transmission, but as viral quasi-species diversify in distinct biological compartments, mutant viruses that are resistant to antibody neutralisation, cytotoxic T cells, or antiretroviral drugs are generated and archived in long-lived cells (ie, viral reservoirs).

Plasma viraemia (top), and dynamic changes of the CD4+ T-lymphocyte compartments (bottom). Primary infection characterised by high plasma viraemia (red line, top), low CD4 cells (green line, bottom), and absence of HIV-1 specific antibodies (orange line, bottom). Viraemia drops as cytotoxic CD8+ T-lymphocytes (CTL) develop (blue line, bottom) and an individual viral-load set point is reached during chronic infection. Viral set points dir er greatly among individuals (eg, red dotted line, top) and predict disease progression. Viral diversity increases through out the disease (closed circles, top). The risk of transmission is highest in the first weeks when viraemia peaks (closed circles, top). GALT=gut-associated lymphoid tissues.

A pronounced depletion of activated as well as memory CD4+ T cells located in the gut-associated lymphoid tissues has been seen in individuals identified early after infection. 67 The preferential depletion of the CD4+ cells in the mucosal lymphoid tissues remains despite years of antiretroviral treatment, a striking observation that contrasts with the fact that the number of CD4+ T lymphocytes in the peripheral blood can return to normal under antiretroviral treatment.

A gradual destruction of the naive and memory CD4+ T-lymphocyte populations is the hallmark of HIV-1 infection, with AIDS being the last disease stage ( figure 4 ). 68 Despite the frequent absence of symptoms during early and chronic phase, HIV-1 replication is dynamic throughout the disease. The half-life of a single virion is so short that half the entire plasma virus population is replaced in less than 30 minutes, 69 and the total number of virions produced in a chronically infected person can reach more than 10¹P particles per day. 69 , 70 The turnover rates of lymphocyte populations are upregulated many fold during HIV-1 infection, whereas cell proliferation decreases once viral replication is reduced by antiretroviral treatment. 71 , 72 Different depletion mechanisms have been proposed, with an emerging consensus favouring generalised immune activation as cause for constant depletion of the CD4+ cell reservoir. 73

Immune activation predicts disease progression 74 and, thus, seems to be a central feature of pathogenic HIV-1 infections. Recently, Nef proteins from SIV lineages that are non-pathogenic in their natural hosts (eg, African green monkeys) have proved to down-regulate CD3-T-cell receptors, resulting in reduced cell activation and apoptosis. 75 HIV-1 Nef fails to quench T-cell activation, possibly leading to the high degree of immune activation seen in infected people.

Understanding the mechanisms that lead to protection or long-lasting control of infection will guide vaccine development by providing correlates of protection. Natural resistance to HIV-1 infection is rare and varies greatly between individuals. Two groups—long-term non-progressors and highly exposed persistently seronegative individuals—have been studied widely to identify innate and acquired protective determinants ( table 1 ). 76 Host resistance factors consist of human leucocyte antigen (HLA) haplotypes, autoantibodies, mutations in the promoter regions, and coding regions of the co-receptors CCR5 and CCR2, as well as the up-regulation of chemokine production ( table 1 ). 76 , 77 Indeed, individuals encoding a truncated CCR5 version (CCR5Δ32) have slower disease progression (heterozygote) or are resistant to CCR5-using viruses (homozygote). 78 The CCL3L1 gene encodes MIP1α, a CCR5 co-receptor ligand and chemokine with antiviral activity. Recent findings show that CCL3L1 gene copies vary individually and higher numbers of gene duplications result in reduced susceptibility to infection, 77 , 79 possibly by competitive saturation of CCR5 co-receptor. Cytotoxic T-lymphocyte responses, helper T-cell functions, and humoral responses are some of the acquired factors that modulate the risk of transmission in highly exposed persistently seronegative individuals, 76 and could also contribute to spontaneous control of replication in long-term non-progressors. The putative protective role of cytotoxic T-lymphocyte activity has been suggested in seronegative sex workers and in some long-term non-progressors. 76 , 80

Some of the host factors affecting susceptibility to HIV-1 infection

HLA=human leucocyte antigen. CCR5=chemokine receptor 5. CCR2=chemokine receptor 2. CCL3L1=CC chemokine ligand like-1, APOBEC3G/3F=apolipoprotein B mRNA editing complex 3.

Mammalian cells are not welcoming micro-environments, but rather deploy a defensive web to curb endogenous and exogenous viruses. HIV-1’s ability to circumvent these defences is as impressive as its efficiency to exploit the cellular machinery. APOBEC3G/3F and TRIM5α are recently described intrinsic restriction factors that are constitutively expressed in many cells. 81 , 82 Both gene loci have been under strong selective pressure throughout primate evolution, 83 indicating an ancient need to neutralise foreign DNA and maintain genome stability that precedes the current HIV-1 pandemic.

APOBEC3 enzymes (A3) belong to the superfamily of cytidine deaminases, 84 a group of intracellular proteins with DNA/RNA editing activity. 84 , 85 Most representatives of the APOBEC3 group have some mutagenic potential and restrict endogenous retroviruses and mobile genetic elements. The deaminases A3G, A3F, and A3B have potent antiviral activity, with the first two being expressed in cells that are susceptible to HIV-1 infection (T-lymphocytes, macrophages). HIV-1 evades APOBEC3 mutagenesis by expressing Vif, which leads to APOBEC3G/3F but not A3B degradation. 42 , 86 – 90

We still need to establish how the mechanisms of DNA editing and antiviral activity are interwoven, since some antiviral activity can be maintained despite defective DNA editing. 91 The early replication block in non-stimulated CD4+ T cells has been attributed to low molecular mass complexes of APOBEC3G. 92 Hypermutated genomes in HIV-1 infected patients 93 and mutations in Vif resulting in abrogated or differential APOBEC3 neutralisation capacity have been described. 94 , 95 The degree to which APOBEC3G/3F mRNA expression predicts clinical progression remains an area of intensive investigation. 96 , 97

Several representatives of the heterogeneous family of tripartite motif proteins (TRIM) inhibit retroviruses in a species-specific manner. 81 , 98 TRIM5α from rhesus macaques and African green monkeys inhibit HIV-1 replication, whereas the human homologue is inactive against SIV and HIV-1, leading to the recorded susceptibility of human cells to both viruses. 81 Rhesus TRIM5α recognises the capsid domain of HIV-1 Gag and manipulates the kinetics of HIV-1 core disassembly within minutes after cell entry. 99 , 100 Thus, experimental approaches to render HIV-1 resistant to rhesus TRIM5α could lead to immunodeficiency viruses capable of replicating in rhesus macaques. Such a non-primate model would allow testing of antiviral treatment and vaccine interventions with HIV-1 viruses instead of SIV or SIV/HIV chimeric viruses.

Clinical management

The diagnosis of HIV-1 infection is based on the detection of specific antibodies, antigens, or both, and many commercial kits are available. Serological tests are generally used for screening. A major advance has been the availability of rapid HIV-1 antibody tests. These assays are easy to do and provide results in as little as 20 minutes, 101 enabling specimen collection and proper diagnosis at the same visit. Rapid tests are important tools for surveillance, screening, and diagnosis, and can be reliably done on plasma, serum, whole blood, or saliva by health-care providers with little laboratory expertise. The two limitations of these serological tests are detection of infection during primary infection when antibodies are absent, and in infants younger than 18 months who might bear maternal HIV-1 antibodies. In these instances direct virus detection is the only option (eg, quantification of viral RNA [standard] or p24 antigen in heat denatured serum [less expensive]).

For staging purposes, measurement of CD4+ cells and viraemia is required. Plasma viral load is widely used to monitor therapeutic success on antiretroviral treatment. Several commercially available tests provide sensitive quantification of plasma HIV-1 RNA copies. The newer versions of the Amplicor and Quantiplex (Roche, Indianapolis, IN, USA, and Bayer Diagnostics, Walpole, MA, USA, respectively) assays have overcome initial suboptimum performance for non-B subtypes. 102 While the viral load determines the rate of destruction of the immune system, the number of CD4+ cells reveals the degree of immunodeficiency and is, therefore, used to assess the stage of infection. CD4+ cell counts together with clinical manifestations (eg, occurrence of opportunistic infections) are key criteria for HIV-1 disease classification. Flow cytometry analysis is the standard method for CD4+ cells quantification.

Standard methods for quantifying viral load and CD4+ cell counts need advanced laboratory infrastructures, and assays require a specimen to be tested within a short time of collection. These requirements pose challenges for resource-constrained settings. The use of dried blood spot specimen has resolved some of the difficulties associated with transportation of samples needed for virological assessments. 103 Measurement of reverse transcriptase activity in plasma samples, simplification of gene amplification methods (eg, Taqman technology), and paper-strip quantification (dipstick assays) might provide cost-effective alternatives for the future. 104 – 106 Similarly microcapilliary flow-based systems, CD4+ chips, or total white counts (panleucocyte gating) provide alternatives for establishment of the level of immunodeficiency in resource-limited settings. 107 – 110

Drug treatment

Antiretroviral compounds.

Antiretroviral treatment is the best option for longlasting viral suppression and, subsequently, for reduction of morbidity and mortality. However, current drugs do not eradicate HIV-1 infection and lifelong treatment might be needed.

20 of the 21 antiretroviral drugs currently approved by the US Food and Drug Administration target the viral reverse transcriptase or protease ( table 2 ). Eight nucleoside/nucleotide analogues and three non-nucleoside reverse transcriptase inhibitors inhibit viral replication after cell entry but before integration. Fixed-dose combination tablets simplify treatment regimens by reducing the daily pill burden, and drugs with long half-lives allow once or twice daily dosing. Eight protease inhibitors prevent the maturation of virions resulting in production of non-infectious particles. The recently approved darunavir (June, 2006) is the first of its class that retains activity against viruses with reduced susceptibility to protease inhibitors. Enfuvirtide targets a gp41 region of the viral envelope and stops the fusion process before the cell is infected. This drug needs to be injected twice daily and its use is reserved for treatment of heavily drug-experienced patients since it can help overcome existing drug resistance. 111 , 112 Development of new antiretrovirals focuses on molecules that target entry, reverse transcription, integration, or maturation. Compounds that have been designed to inhibit resistant viruses are urgently needed since many patients treated during the past decades harbour viral strains with reduced susceptibilities to many if not all available drugs ( table 3 ).

Antiretroviral drugs currently approved by US Food and Drug Administration

Drugs belong to five drug classes and target three dir erent viral steps (entry, reverse transcription, or protease). Availability of these drugs in resource-limited countries is subject to country specific licensing agreements.

Antiretrovirals currently in phase II/III of clinical development

The goal of antiretroviral treatment is to decrease the morbidity and mortality that is generally associated with HIV-1 infection. A combination of three or more active drugs is needed to achieve this aim in most patients. Effective treatment returns to near normal the turnover rates of both CD4+ and CD8+ T-cell populations. 72 Potent but well tolerated drugs with long half-lives and simplified regimens improve the options for first-line and second-line chemotherapeutic interventions.

Combination antiretroviral treatment

High rate of viral replication, low fidelity of reverse transcription, and the ability to recombine are the viral characteristics that lead to the diversity of HIV-1 species (quasi-species) in chronically infected individuals. This high genetic variability provided the rationale for highly active antiretroviral treatments (HAART). By combination of several potent antiretroviral agents, viral replication is suppressed to such low levels that emergence of drug resistant HIV-1 variants was, if not prevented, at least delayed. By doing so, CD4+ T-lymphocyte numbers increase, leading to a degree of immune reconstitution that is sufficient to reverse clinically apparent immunodeficiency. Widespread introduction of HAART in industrialised countries resulted in a striking decrease in morbidity and mortality, putting forward the hope that HIV-1 infection can be transformed into a treatable chronic disease. 113 – 115

A set of criteria composed of plasma viraemia concentration, absolute or relative CD4+ cell counts, and clinical manifestations, is used to recommend initiation of HAART. The benefits of treatment clearly outweigh the potential side-effects in patients with clinical signs of immunodeficiency (eg, AIDS defining illnesses) or with CD4+ numbers less than 200 per μL (recommendation of US Department of Health and Human Services, October, 2005). However, the best time point to begin treatment remains controversial in asymptomatic patients with modest depletion of CD4+ T cells (eg, more than 350 per μL) and modest levels of viraemia (eg, less than 100 000 copies per mL). 116 Studies with clinical endpoints supporting the validity of early versus late interventions in asymptomatic patients are difficult to do and insufficient clinical data are currently available. Early depletion of gut CD4+ T lymphocytes, 117 increasing viral diversity, and the poor regenerative abilities of key populations of the immune system provide arguments for beginning treatment as early as possible. The wide application of this principle is restricted by long-term drug toxicities that lead to reduction of quality of life, and by treatment costs. Toxicities (eg, renal, hepato, mitochondrial), metabolic changes (eg, lipodystrophy, diabetes mellitus), and immune reconstitution disease are some of the long-term problems that complicate decade-long HAART. 118 – 121

One strategy addressing life-long daily compliance to HAART has been structured treatment interruptions. The rationale for this approach was based on the premise that the body’s own immune system could keep the virus in check if exposed to a very modest level of viral replication. If successful, this strategy could limit drug toxicity and reduce treatment costs. 122 Although preliminary findings for this strategy were mixed in terms of benefits, 123 – 125 the recent early closure of the SMART trial was based on increased morbidity and mortality in the treatment interruption arm. 126 Thus, in the absence of clinical benefits, most investigators strongly discourage treatment interruptions except as needed to address treatment intolerance.

HAART in resource-constrained settings

The transformation of AIDS into a chronic disease in industrialised countries has yet to be realised in resource-constrained settings. Access to HAART is an absolute humanitarian necessity to avert mortality in people who are central to the future survival of their countries. 127 Despite restricted health infrastructures and diverse co-morbidities in these regions, remarkable therapeutic success rates have been shown, with adherence rates at least comparable with those reported in industrialised countries. 128 – 131 WHO and UNAIDS treatment guidelines focusing on resource-limited settings suggest use of standard first-line regimen followed by a set of more expensive second-line options 132 and proposes the use of standardised decision-making steps (eg, when to start, to substitute for side-effects, to switch for virological failure). 132 , 133 In many countries, treatment options are limited not only by the costs of HAART but also by restrictive licensing policies, and current estimates suggest that 80% of people infected with HIV-1 with a clinical need for treatment do not yet have access to antiretroviral drugs. 1 Thus, efforts and strategies to further scale up treatment access are crucial, 134 – 137 since antiretroviral treatment is also an effective intervention for prevention. 138

Drug resistance

Emergence of drug resistance is the most common reason for treatment failure. Insufficient compliance, drug side-effects, or drug-drug interactions can lead to suboptimum drug concentrations, resulting in viral rebound. Viral resistance has been described to every antiretroviral drug and therefore poses a serious clinical as well as public-health problem. 139 HIV-1 subtypes differ in the sequence of mutations leading to drug resistance, and some naturally occurring polymorphisms might actually modulate resistance. 140 , 141 Drug-resistant HIV-1 is transmissible and can be detected in up to 20% of newly infected individuals in countries with broad access to antiretrovirals. 34 The prevalence of drug resistance in the untreated population remains low in regions with poor access to treatment. 142

Short-term antiretroviral-based interventions are effective in prevention of mother-to-child transmission. However, these interventions could result in drug resistant viral variants in the mother, baby, or both. 143 Around half the women who received one dose of nevirapine to prevent mother-to-child transmission harbour viruses resistant to non-nucleoside reverse transcriptase inhibitors (NNRTI). 144 , 145 These resistant viruses replicate efficiently and can be transmitted by breast milk, 146 and minor resistant populations present long after the intervention can possibly decrease the effectiveness of subsequent NNRTI-based treatment regimens. 147 The combination of short-course zidovudine, lamivudine, and nevirapine prevents peripartum transmission while reducing the risk of nevirapine resistant viruses. 148

Viral reservoirs

Viral reservoirs consist of anatomical sanctuaries and a small pool of infected long-lived memory T lymphocytes. HIV-1 latency in long-lived cell populations (eg, memory T lymphocytes, macrophages) poses an obstacle to eradication because current antiviral combination treatments fail to eliminate integrated proviruses from resting cells. Different strategies, including immune-modulatory molecules (interleukin 2, anti-CD3 mAb, interleukin 7), have been used to reactivate resting cells in the setting of HAART. Histone deacetylase-1 inhibitors, like valproic acid, release an inherent transcriptional block and by doing so facilitate viral long terminal repeat-driven expression. 149 Augmenting standard antiretroviral treatment with enfuviridine and valproic acid reduced the number of latently infected CD4+ T cells (29–84%), but to establish the relative contribution of each drug with respect to the final outcome is difficult. 150

Mother-to-child transmission

Prevention of mother-to-child transmission has seen advances in both industrialised and resource-constrained settings. 151 – 153 Intrapartum transmission has been reduced by increasing access to interventions such as one dose of nevirapine to mother and newborn baby. 154 Concerns about drug-resistant viral strains have led to several trials with combination treatments to reduce transmission during the intrapartum period. 148 , 152 , 155 In some settings, elective delivery by caesarean section can further reduce HIV-1 transmission during the intrapartum period, but the benefits of the intervention could be countered by post-partum sepsis and increasing maternal mortality. 156

Because HIV-1 can be transmitted by breastfeeding, replacement feeding is recommended in many settings. Poor access to clean running water precludes, however, the use of formula feeding under these circumstances, 157 and exclusive breastfeeding with abrupt weaning is one option for reducing transmission. 158 A potential novel intervention still being tested is the daily use of antiretrovirals during breastfeeding. More attention is starting to focus on the pregnant mother, especially initiation of antiretroviral therapy in mothers with low CD4+ counts during pregnancy and thereafter. 159 , 160 Only limited data are available regarding the health of uninfected children born to HIV-1-positive mothers. 161 In a European cohort of exposed-uninfected children, no serious clinical manifestations were apparent, at least in the short term to medium term (median follow-up 2 years). 162

Sexual transmission

Reduction of heterosexual transmission is crucial for control of the epidemic in many parts of the world. 1 , 163 Prevention is achieved through reduction in the number of discordant sexual acts or reduction of the probability of HIV-1 transmission in discordant sexual acts. The first can be achieved through abstinence and sex between concordantly seronegative individuals. Abstinence and lifelong monogamous relationships might not be adequate solutions for many people and therefore several interventions aimed at lowering the risk of transmission per discordant sexual act are in the process of clinical testing. Male and female condoms provide a proven and affordable prevention option. 164 , 165 In combination, these options are also more commonly referred to as the ABC (abstinence, be faithful, condom use) approach.

Other biomedical prevention interventions include male circumcision, antiretrovirals for prevention (eg, pre-exposure or post-exposure), chemoprophylactic treatment of herpes simplex virus-2 (HSV-2), microbicides, and vaccines. Results from one of three independent phase III male circumcision trials underway in South Africa, Kenya, and Uganda has helped to allay some of the ambivalence around the protective effect of male circumcision. 8 , 166 The findings from the South African trial show a 60% protective effect of male circumcision. 167 The possible mechanism relates to the fact that the foreskin has apocrine glands that secrete lysozymes but also Langerhans cells expressing CD4 and other receptors. 168 , 169 These skin-specific dendritic cells can uptake virus and are believed to play a part in transport of the virus to susceptible T cells. Immunofluorescence studies of foreskin mucosa suggest that these tissues might be more susceptible to HIV-1 infection than cervical mucosa. 170 Findings from this proof-of-concept trial need to be compared with evidence from the two trials still underway in Kenya and Uganda, and to acceptability data, behaviour change after circumcision, surgical complication rates, and logistics of undertaking the procedures before policy formulation and wide-scale access as a prevention strategy. 171 – 173

Since high plasma viraemia increases the risk of transmission by as much as an order of magnitude, 21 does reducing viral load in the infected partner through, for example, antiretroviral treatment reduce the risk of HIV-1 transmission in the uninfected sexual partner? A trial to explore this question is currently being run jointly by the HIV Prevention Trials Network ( www.hptn.org ) and the Adult Clinical Trials Group. Mathematical projections estimate up to 80% HIV-1 reduction, 174 , 175 but scarce observational data currently exist. 176 Post-exposure prophylaxis is recommended after occupational (eg, needle stick) 177 and non-occupational (eg, rape, sexual abuse) 178 exposure, although data for efficacy and optimum drug combinations are few. 179 Some clinical trials assessing the benefits of once daily pre-exposure chemoprophylaxis with antiretroviral compounds with long biological half-life (eg, tenofovir) have been put on hold or stopped. 175 , 180 Neither the overall idea of pre-exposure prophylaxis nor the drug itself, which is well tolerated, was at the root of the protests. Concerns were centred on clinical trials in resource-poor settings and the perceived scarcity of adequate interventions protecting these vulnerable populations.

HSV-2 might increase both the risk of transmitting and acquiring HIV-1. 181 , 182 Antivirals (eg, aciclovir, valaciclovir) are effective in reducing viral shedding 183 – 185 and HSV-2 transmission in discordant heterosexual couples. 182 The future of HSV-2 prevention might reside in the vaccine that is currently under development. 186 Whether prophylactic use of aciclovir in populations with high HSV-2 prevalence and incidence rates results in reduced HIV-1 incidence rates remains unresolved but several trials addressing this issue are underway, including HPTN039.

Gender disparities lie at the centre of women’s vulnerability. Prevention options need to be provided that can be used by women independently of their male sexual partner’s knowledge or consent. 187 Notwithstanding that redressing these disparities is a long-term challenge, several preventive interventions can be implemented in the interim on the basis of our incomplete understanding at a biological level of HIV-1 risk for women. For example, there seems to be a correlation between levels of sexual hormones (eg, progesterone) and transmission risk. 188 Observational studies also highlight the relation between abnormal vaginal flora and increased risk of HIV-1 infection. 189 , 190 The high prevalence of vaginal infections such as bacterial vaginosis (30–50%), vulvovaginal candidosis (10–13%), and trichomonas vaginalis (7–23%) in African women is associated with a substantial risk of HIV-1 acquisition. 189 In addition to increasing access to female condoms and treatment of other sexually transmitted infections, trials are underway to assess the use of other barrier methods such as cervical caps, invisible condoms, diaphragms, and diaphragms combined with micro bicides. 190 The control of vaginal infections is a potentially important method for decreasing HIV-1 acquisition that has yet to be tested. Periodic presumptive treatment for vaginal infections is being explored as an HIV-1 prevention strategy. 191

Microbicides

Microbicides are an additional important biomedical intervention technology that is covert and under women’s control. 192 These topical products potentially could be used to prevent rectal and vaginal transmission of HIV-1, but proof of concept has been elusive. Although the three phase III trial results of the first microbicidal product (nonoxynol-9) done in the mid-1980s and 1990s did not show protective effects, 193 , 194 they have informed the medical knowledge in terms of product selection, clinical testing, and safety assessments. The past 5 years have seen major advances in investment and product development. 66 , 195 , 197 Early clinical testing of multiple products including the launch of advanced clinical trials for five different products is continuing ( table 4 ). The development of antiretroviral gels increased the specificity of these third generation microbicides in relation to surfactants, vaginal enhancers, or entry inhibitors that have dominated the product pipeline so far ( figure 5 ). The first antiretroviral gel to undergo early testing is tenofovir gel, and the findings in terms of safety profile, tolerance, low systemic absorption, and slight adverse events are promising. 192 As with vaccines, a major obstacle is the absence of a surrogate marker of protection. Additional challenges are adherence to product use and the high rates of pregnancy in trial participants.

N9=nonoxonol-9. CS=cellulose sulphate.

Summary of microbicides currently undergoing advanced clinical testing

A safe, protective, and inexpensive vaccine would be the most efficient and possibly the only way to curb the HIV pandemic. 198 Despite intensive research, development of such a candidate vaccine remains elusive. Safety concerns prohibit the use of live-attenuated virus as immunogen. 199 Many different approaches with recombinant technologies have been pursued over the past two decades. Initially, efforts were focused on generating neutralising antibodies with recombinant monomeric envelope gp120 (AIDSVAX) as immunogen. 200 , 201 This vaccine did not induce neutralising antibodies and, not unexpectedly, the phase III trials failed to show protection. 202 , 203 Antibody mediated HIV-1 neutralisation is complicated by the high genetic diversity of the variable Env regions, epitopes masked by a carbohydrate shield (glycosylation), and conformational or energetic constraints. 204 Since CD8 T-cell responses control to some extent viral replication in vivo, recent vaccine development has focused on eliciting cellular immune responses. Overcoming pre-existing immunity against replication incompetent immunogenic vectors (eg, recombinant adenovirus type 5) is one of the challenges. 205 Safety and immunogenicity studies using replication defective vaccine vectors are continuing after preliminary studies in non-human primates showed some protection. 204 The immune system generally fails to spontaneously clear HIV-1 and the true correlates of protection continue to be ill defined. 198 , 206 However, the general belief is that approaches aimed at eliciting both humoral and cell mediated immunity are most promising to prevent or at least control retroviral infection. 198

Conclusions

An important gateway to both prevention and care is knowledge of HIV-1 status. 207 Fear of knowledge of status, including stigma and discrimination, has discouraged many from seeking voluntary counselling and testing services. 208 As access to antiretroviral interventions (prevention of mother-to-child transmission, antiretroviral treatment) increases, the opportunities for HIV-1 testing will grow and create opportunities for a prevention-care continuum, with the voluntary counselling and testing services as a point of entry. These changes will result in a shift in prevention efforts from a focus on individuals not infected with HIV-1 to a more effective continuum of prevention that includes uninfected, recently infected, infected, and asymptomatic people, as well as those with advancing HIV disease and on antiretroviral therapy.

HIV/AIDS is an exceptional epidemic that demands an exceptional response. Much progress has been made in a short space of time, despite many scientific and programmatic challenges ( figure 6 ). In the absence of a protective vaccine or a cure, prevention and access to antiretroviral treatments are the best options to slow down the HIV-1 pandemic. Broad implementation of these principles needs improved infrastructures in resource-constrained regions, which have been and will continue to be most affected. The fact that HIV-1 is predominantly sexually transmitted and disproportionately affects populations that are already socially or economically marginalised, or both, poses many ethical, social, economic, and political challenges.

Estimates place the cross species transmission events leading to the worldwide spread of HIV-1 to the early decades of the 20th century. Numbers circled by a hexagon identify the specific year of an event. PEPFAR=President’s Emergency Plan for AIDS Relief.

In view of the immediacy of the problem, and the fact that both research and programmes are mainly funded by the public sector, there is a greater demand from civil society for co-ownership of research and accountability for use of public funds. On the one hand, this co-ownership defines a changing role and responsibility of science in society, and on the other hand, shows a necessary synergy between activism and science. This partnership has been invaluable for antiretroviral drug development, treatment access in resource-constrained settings, and the scale-up of interventions to reduce mother-to-child transmission.

The increasing number of infected women and the disproportionate burden of infection in resource-constrained settings creates a scientific imperative to ensure research is done for people and in settings who stand to benefit most. The most affected countries face many other economic, political, and development challenges, which have raised issues in undertaking multicentre and multicountry research. Research addressing women-specific topics (such as effect of sexual hormones on transmission and disease progression, viral diversity, and antiretroviral potency) and women-specific prevention interventions including microbicides is crucial. We are probably at one of the most hopeful and optimistic points in our response to the pandemic. There is definitely more attention being directed to HIV-1, more resources ( panel ), more civil society mobilisation, more governments speaking up, more possibilities for treatment, and more evidence about what prevention and treatment strategies will work than in previous years. The unrelenting growth of the pandemic tells us that current strategies are not enough. Clearly, we need to do some things differently, while also increasing the scale and magnitude of current strategies in keeping with the pandemic.

PanelOnline resources

Epidemiology.

http://www.unaids.org/en/HIV_data/default.asp

Treatment recommendations

Centers for Disease Control and Prevention

http://www.cdc.gov/hiv/topics/treatment/index.htm

HIV-1 drug resistance

Stanford University HIV Drug Resistance Database

http://hivdb.stanford.edu/index.html

International AIDS Society–USA

http://www.iasusa.org/resistance_mutations/index.html

Microbicide

Alliance for Microbicide Development

http://www.microbicide.org

HIV Prevention Trials Network

http://www.hptn.org/index.htm

International AIDS Vaccine Initiative

http://www.iavi.org

Search strategy and selection criteria

A comprehensive literature review was undertaken by searching the PubMed database online, for English language publications between January, 2000, and June, 2006. The database search terms included keywords such as “HIV/AIDS”, “epidemiology”, “prevention”, “pathogenesis”, “HSV-2”, “male circumcision”, “PMTCT”, “scaling up treatment”, “resource constrained settings”, “antiretroviral pre-exposure prophylaxis”, “HAART”, “restriction”, “host factor”, “HIV pathogenesis”, “resistance”, “latency”. Various combinations of these words were entered. All duplicate articles were removed. A subset of relevant articles was chosen and full-text manuscripts were summarised.

Acknowledgments

We thank P D Bieniasz, W Cates, L Chakrabarti, C Cheng-Mayer, J Coovadia, H Gayle, P A Fryd, R Gray, S Abdool Karim, L Kuhn, K Mayer, P Mane, L C F Mulder, L Myer, and M Wawer for helpful discussions. M Boettiger and C Baxter assisted with literature searches. This work was supported by NIH grant RO1AI064001 (VS), by grant 1 U19AI51794 (QAK) from CAPRISA that forms part of the Comprehensive International Program of Research on AIDS (CIPRA) funded by the National Institute of Allergy and infectious Disease (NIAID), National Institutes of Health (NIH) and the US Department of Health and Human Services (DHHS) and grant D43 TW00231 (QAK) from the Columbia University-Southern African Fogarty AIDS International Training and Research Program.

Conflict of interest statement

D D Ho sits on the scientific advisory boards for Monogram, Osel, Achillion, Valiant, Oyagen, Lavipharm, and XTL. Products or work from these companies are not discussed in the review. He holds patents on vaccine candidates. The other authors declare no conflict of interest.