Hurdles in HIV Vaccine Development

May 17, 2024
Science Magazine

A sore throat, fever, muscle pain, and sudden fatigue are all symptoms of a decades-old global killer: AIDS. More than forty million people have died from AIDS-related illnesses since the early 1980s. To put that figure in perspective, the COVID-19 pandemic has claimed the lives of roughly seven million people since March 2020. Thankfully, COVID-19 vaccine options have helped curb the virus's mortality rate. AIDS, on the other hand, still has no vaccine or cure despite decades of research and development. 

The First Outbreak in the United States 

Caused by the human immunodeficiency virus (HIV), acquired immunodeficiency syndrome (AIDS) was first reported in the United States in 1981. In the disease’s first documented appearance in the country, a man was admitted to the Clinical Center at the National Institutes of Health (NIH) displaying severe immunodeficiency. In an article soon after, the Centers for Disease Control (CDC) described five cases of a rare lung function called Pneumocystis carinii pneumonia in previously healthy gay men. None of them survived. Following this publication, doctors around the country began reporting cases of Kaposi’s sarcoma, an aggressive type of rare cancer caused by Human Herpesvirus-8, that seemed most prevalent in people with immunodeficiencies and gay men in particular. How were all of these cases connected? 

By the end of 1981, the United States had 337 reported cases of this mysterious illness and 130 deaths (including 16 children), representing a mortality rate of 40%. Because most reported cases were in gay or bisexual males, this deadly disease soon became known as “gay-related immune deficiency” (GRID), a derogatory term. While scientists now know that HIV infection is not limited to gay or male individuals, at the time that AIDS emerged its causes and modes of transmission were unknown. There was also no way to test for the disease. These barriers to understanding how the virus spread opened the way for discrimination against groups who were disproportionately affected by HIV/AIDS such as the LGBTQ+, Black, and Latino communities, as well as intravenous drug users. The stigma surrounding AIDS caused many people to refuse interaction with HIV-positive patients due to fears that they would contract the disease. 

Transmission of HIV

The case of Ryan White was a landmark in the HIV/AIDS epidemic. Born with hemophilia, White was unable to produce blood clotting factors and required regular blood transfusions. During one of his transfusion sessions at age 13, White received blood contaminated with HIV and became ill. After he was diagnosed with AIDS, the school board prevented him from returning to class, and people would curse at him and call him “queer” even though his diagnosis was unrelated to sexual orientation. White’s story made national headlines as he became a figure in the HIV/AIDS campaign in the United States. He changed public perception of the disease and helped improve medical practices for patients needing transfusions. White died at age 18, just before graduating high school. 

It is now known that HIV isn’t an airborne disease and is usually transmitted through unprotected sex and contaminated needles.

Above: Ryan White. Image courtesy of MPI/Getty Images.

Many members of the queer community in the 1980s have recalled through interviews how terrifying it was to watch close friends getting sick and slowly dying with no effective treatment. Without treatment options, many HIV-positive individuals refused testing for peace of mind—and to avoid demonization and ostracism. Others resorted to ineffective pseudoscientific methods in search of potential cures.

The Rise of Advocacy Groups

Many criticize the NIH's slow response to the AIDS epidemic. The organization’s slow release of funding for HIV/AIDS research and the role its scientists played in creating stigma against the disease resulted in countless preventable deaths. Due to government inaction and lack of funding during the 1980s economic recession, many grassroots movements and alliances formed to take matters into their own hands. The AIDS Coalition to Unleash Power (ACT UP) was the first international organization founded to bring attention to the epidemic. The 2017 French movie 120 Beats per Minute tells the story of ACT UP in Paris and its role in pressuring the government for affordable medication, continued vaccine research, and the fight against social stigma for people living with HIV/AIDS. This film faithfully depicts how these grassroots movements run by volunteers had a real impact on communities. Although there was not always a consensus among all members, ACT UP was a well-organized machine with committees for outreach, finance, treatment, and protest. The organization carefully planned demonstrations and actions to be as impactful as possible. 

Above: Act Up Protest during the Gay and Lesbian Pride march in New York City on June 26, 1988. Image courtesy of The New York Historical Society/Getty Images. 

The End of AIDS?

The first glimpse of hope for HIV-positive patients came in 1987 when the first HIV medication became available: AZT (azidothymidine or zidovudine). AZT is an antiretroviral drug that interferes with the replication of retroviruses like HIV by inhibiting reverse transcriptase: an essential enzyme in their DNA synthesis process. If the virus cannot synthesize DNA, it cannot make more copies of itself and spread. Doctors prescribed AZT to treat sick patients and limit mother-to-child transmission during pregnancy. However, HIV quickly developed resistance to the drug, leading to some patients not responding to AZT treatment. As other classes of antiretrovirals rolled out that tackled other stages of the viral replication cycle, the new standard of care became known as HAART, or highly active antiretroviral therapy.

HAART is now called ART and is still the preferred method used today. It relies on a mix of antiretroviral drugs instead of only one. With HAART, the body can maintain the viral load in undetectable amounts and patients live relatively normal lives with low chances of HIV transmission to others. Newer strategies like PrEP (pre-exposure prophylaxis) and PeP (post-exposure prophylaxis) have also greatly reduced disease transmission. Patients take PrEP before condomless sex or contact with contaminated needles to avoid infection, and PeP is used in emergencies after a potential exposure. Both of these methods involve antiretroviral drugs and prevent HIV replication in the host. 

Above: Truvada, a common PrEP medication. Image courtesy of Getty Images News/Getty Images.

A Growing Challenge

Despite advances in AIDS treatment and prevention in the last 40 years, scientists are still searching for an effective vaccine. What scientists predicted would take a few years to be accomplished has taken decades longer. Although several attempts have reached human trials, none have shielded all individuals with long-lasting protection. What are the major obstacles in the way of new treatments?

In an interview with Dr. Michael Anthony Moody, professor at the Duke School of Medicine and director of the Duke CIVICs Vaccine Center, he points out some important points that have hindered vaccine development:

The first obstacle is the structure of HIV. Each virus comprises an outer layer with viral proteins (like gp120 and gp41). These proteins are critical players in host infection, as they associate with specific host cell membrane receptors. Much of the HIV research to date has focused on characterizing these viral envelope proteins (gp120 and gp41) and the human cell receptors (CCR5 and CXCR4) to uncover the mechanisms of this interaction. 

Above: HIV scheme. Image courtesy of Eric Rossi.

Above: HIV and human T-cell interaction scheme. Image courtesy of Angela Wahl.

Second, researchers must also consider how HIV can integrate its genes into the host genome, and remain latent, or dormant, for long periods of time. This latency means that vaccines need to prevent not only viral replication but also infection to avoid the integration of the HIV genome into host cells—HIV latency can cause the unexpected reemergence of the virus even in patients on potent ART.

A third obstacle is that HIV has an extremely high mutation rate, meaning that its genetic material changes slightly after every replication. With time, these mutations create strains that better evade the selective pressure of the immune system and have led to different viral groups, each with its distinct mutations. So far, scientists have classified 12 main groups and various recombinant forms derived from crossings between them. For a vaccine to be effective, researchers must design an immunogen that can offer protection against several of these groups, as HIV infection usually presents itself with different strains simultaneously. Current research has largely focused on producing broadly neutralizing antibodies (bNAbs) that attack conserved regions among these strains, which despite mutations are still preserved. Unfortunately, bNAbs have proven to be hard to elicit in our immune system and often display polyreactivity and autoreactivity, meaning that they have an affinity with molecules unrelated to HIV and sometimes even molecules from the host. Researchers are unsure if these responses are essential in affinity maturation, or the intensification of antibody attraction to pathogens.

Future Directions

Recently, Duke researchers Dr. Ashley Bennett and Dr. Rory Henderson of the Duke Human Vaccine Institute published a study that identified microsecond changes in the HIV envelope protein that help it bind to host cells. This envelope protein displays an open and a closed conformation and is essential for the fusion of the virus with host cells. Using an electron accelerator and increasing temperatures, they observed previously unknown intermediate structural transitions of these viral envelope proteins. Understanding the details of this process may enable researchers to develop even more efficient antiretroviral therapies.

Moreover, Dr. Bennett emphasized the importance of tackling this virus from different angles and harnessing continuous collaboration among researchers, as no one can tell with certainty where a cure for HIV/AIDS will lie.

After several pandemics and epidemics, government health organizations and scientists still have much to learn about disease control. At Duke and in the Research Triangle, the Human Vaccine Institute and the Center for Research in Emerging Infectious Diseases have contributed to HIV/AIDS research since the 1980s and are leaders in vaccine testing and innovation. These research groups have now expanded their scope to prepare for future breakouts. Even though researchers are still searching for an HIV vaccine, numerous advancements in protein engineering, genome therapies, and other medical technologies have emerged from this process and have been applied to treat other diseases. Further, this decades-long research endeavor has taught scientists, doctors, patients, and the public to see one another with greater empathy, compassion, and solidarity.

Vinicius Fu

Vinicius (Trinity ’26) is originally from São Paulo, Brazil and majoring in Biology. He currently works in the Collier Lab researching peptide nanofibers. Vinicius loves trying new restaurants and going on hikes with his friends. In Vertices, he enjoys the freedom to write about research topics he wouldn't otherwise explore.

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