Attacking HIV At Its Core

IRP Researchers are Developing Vaccines Targeting the ‘Achilles Heel’ of a Wiley Infectious Threat

By Melissa Glim

Monday, December 2, 2024

In the 40 years since HIV, the virus behind AIDS, was first definitively identified, treatments have changed the disease from a sure death to a long-term chronic illness. Yet, as we passed the 36^th annual commemoration of World AIDS Day on December 1, it remains a dangerous health threat. Consequently, many researchers are attempting to develop vaccines to prevent or treat HIV, including IRP senior investigator Barbara K. Felber, Ph.D. Dr. Felber has been pursuing an effective vaccine since the discovery of HIV in the early 1980s using a unique approach that is not only making headway toward that important goal, but also offering insights into other infectious diseases, as well as cancer immunotherapy.

“In contrast to the recent COVID pandemic and the rapid development of useful vaccines for COVID and other diseases, an HIV vaccine has been very difficult to develop,” Dr. Felber says. “In the 1980s, the field expected creating an HIV vaccine would be easy. It’s a virus encased in an envelope that we thought we could use to create a molecule that will induce an immune response, and the problem would be solved.”

Of course, now we know that wasn’t the case. The reason is the complexity of the virus itself. Traditional vaccines for viruses work by training the immune system using a decoy — a weakened or inactivated version of the virus or a part of the virus. The body practices recognizing and attacking the non-infectious version so when the real virus comes along, the body knows what to do. Unfortunately, some viruses, like HIV, mutate and evolve too quickly or are too well-protected for this approach to work.

“Its envelope is covered in sugars that stick out like a lollipop, which makes it difficult for the immune system to find a target that can be recognized, attacked, and neutralized,” Dr. Felber explains. “This has been the big stumbling block in the field. What’s more, the ‘easy’ targets the virus offers mutate rapidly, making this type of defense useless.”

These complexities have forced researchers to develop different types of vaccines, such as vaccines based on genetic material like DNA and RNA. Such vaccines have been Dr. Felber’s focus since coming to NIH in 1985. The vaccines Dr. Felber works on contain nucleic acids — the building blocks that make up DNA and RNA — and cytokines, which are small proteins involved in cell signaling and the immune response that boost the immune system’s reaction to the vaccine. By training the immune system to recognize the genetic features that are consistently found in HIV, such vaccines get around the fact that HIV has so many different, ever-shifting forms that can present a variety of signals to the immune system, many of which turn out to be red herrings.

“Essentially, using traditional vaccines, you make an army of immune cells with the wrong or inefficient weapons, so we want to train the immune system to actually see and attack the critical components, the ‘Achilles’ heel,’ of the virus,” Dr. Felber explains. 

Over several years, Dr. Felber’s team and its collaborators developed ways to boost production of nucleic acids and improve methods of delivering them to human tissues. This made it possible to develop DNA and RNA vaccines that cause the body to produce the appropriate components of HIV that help teach the immune system to target and destroy real HIV, just like RNA vaccines for COVID cause the body to produce the COVID Spike protein, which the virus uses to infect cells. Dr. Felber’s team also boosts the vaccine’s action by adding a cytokine called interleukin-12 (IL-12). In animal studies, the IRP researchers found this technique improved immune protection against HIV by increasing the strength and longevity of the immune response.

Moreover, Dr. Felber’s research focuses specifically on ‘highly conserved’ HIV proteins that have not changed much despite the virus’ continued mutation over the years. HIV groups, called clades, are highly diverse, so these conserved proteins must be evolutionarily important to the virus if they remain consistent over time. However, the researchers also need to ensure their vaccine does not trigger responses to the more variable proteins produced by each virus clade, as those proteins could act as decoys to mislead immune cells and prevent a successful immune response. 

Her laboratory has developed just such a vaccine, which the group recently tested in clinical trials through the HIV Vaccine Trials Network (HTVN), which is partially funded by NIH. HTVN is a collaboration among research centers around the world that not only tests vaccines and other interventions in places like Malawi, South Africa, Thailand, and Peru, but also works to build up the physical, labor, and expertise infrastructure to support continued research. 

“When HTVN started, research institutions in many places didn’t have the scientific approaches, the machines, the knowledge, or the money to do this kind of research, nor did they have the level of education needed,” Dr. Felber says. 

That clinical trial showed that Dr. Felber’s vaccine, which targets an important HIV protein along with seven highly conserved HIV components, provided more focused and strong immunity against HIV than a vaccine that targeted only that one important HIV protein.¹ Two other clinical trials, one published earlier this year² and another pending publication, have also shown the power of the Felber lab’s vaccine approach for controlling the virus in people already infected with HIV. 

What’s more, Dr. Felber and her research team have identified a form of the cytokine interleukin 15 (IL-15), called heterodimeric IL-15 (hetIL-15), which greatly increases the ability of vaccine-induced immune cells to find their way to HIV-infected lymph nodes and destroy infected cells.³ The approach has not only generated strong interest as a treatment for HIV, but has also shown promise for treating tumors in animal studies.

“What we need to do is supercharge killer T cells so they can destroy any infected cells,” Dr. Felber says. “We and other groups are using IL-15 in this configuration to mobilize and strengthen the killer T cells to go to the right place and attack the invader, be it a tumor or HIV. I believe this strategy will be important for cancer immunotherapy and the emerging era of cancer vaccines.”

As Dr. Felber and her research team develop and test their vaccines, they continue to work closely with the HTVN. The organization has helped train researchers and staff, set up laboratories, and create a generation of people with the knowledge and skills to conduct HIV research — resources that can only be a boon towards the fight against a persistent and tricky infectious disease that harms people all over the world.

“I think COVID taught everybody — or should have taught everybody — that we’re not protected by geography,” Dr. Felber says. “We have to be open-minded and we have to have connections and channels open for broad collaborations, which are essential to reach our goal of developing an HIV vaccine.”

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References:

[1] Kalams SA, Felber BK, Mullins JI, Scott HM, Allen MA, De Rosa SC, Heptinstall J, Tomaras GD, Hu J, DeCamp AC, Rosati M, Bear J, Pensiero MN, Eldridge J, Egan MA, Hannaman D, McElrath MJ, Pavlakis GN, HIV Vaccine Trials Network 119 (HTVN 119) Study Team. Focusing HIV-1 Gag T cell responses to highly conserved regions by DNA vaccination in HVTN 119. JCI Insight. 2024;9(18):e18081 doi: 10.1172/jci.insight.180819.

[2] Jacobson JM, Felber BK, Chen H, Pavlakis GN, Mullins JI, De Rosa SC, Kuritzkes DR, Tomaras GD, Kinslow J, Bao Y, Olefsky M, Rosati M, Bear J, Hannaman D, Laird GM, Cyktor JC, Heath SL, Collier A C, Koletar SL, Taiwo, BO, Tebas P, Wohl, DA, Belanzauran-Zamudio PF, McElrath MJ, Landay AL, ACTG 5369 Study Team. The immunogenicity of an HIV-1 Gag conserved element DNA vaccine in people with HIV and receiving antiretroviral therapy. AIDS, 38:963-973. 2023. doi: 10.1097/QAD.0000000000003804.

[3] Stellas D, Karaliota S, Stravokefalou V, Bergamaschi C, Felber BK, Pavlakis GN. Tumor eradication by hetIL-15 locoregional therapy correlates with an induced intratumoral CD103^intCD11b⁺ dendritic cell population. Cell Rep. 2023; 42(5): 112501. doi: 10.1016/j.celrep.2023.112501.

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