A small number of people living with HIV are able to durably suppress the virus after stopping antiretroviral therapy, a phenomenon that has long interested researchers searching for a functional cure. A new study from the Gaiha Lab at the Ragon Institute, published in Science Translational Medicine, helps explain why, and points to a specific type of immune cell that could be the key to designing better therapies.

The research focuses on people known as post-treatment controllers, or PTCs, who make up roughly 4% of people living with HIV and who can suppress the virus for months or years after stopping their daily medication. Until now, it wasn’t clear what role CD8⁺ T cells (the cells of the immune system that kill virus-infected cells) played in sustaining this control. 

Earlier work had suggested these cells were not a substantial factor for post-treatment controllers, in contrast to their well-documented role in a separate, and even rarer group known as elite controllers (who suppress HIV without ever needing treatment).

The team assembled a diverse group of post-treatment controllers, elite controllers, and non-controllers and examined how their CD8⁺ T cells behaved when exposed to HIV. While the number of CD8⁺ T cells in post-treatment controllers initially appeared unremarkable, these cells had a remarkable ability to multiply and develop into effective virus killers once they encountered the viral proteins. This expansion capability was comparable to what was observed for elite controllers and far exceeded what was seen in people who lost control of the virus after stopping therapy.

Upon further examination, the team found that CD8⁺ T cells in post-treatment controllers exhibited a distinctive profile known as a stem-like memory state. These cells function almost like a reserve force, retaining the flexibility to respond quickly and robustly when the virus reappears.

The researchers also looked at the reservoir of virus within these individuals – the pool of HIV integrated into host cells that persists in the body during treatment. Notably, post-treatment controllers harbored reservoirs with less genetic diversity than non-controllers, meaning the virus had developed fewer ways to evade CD8⁺ T cells when targeted. Combining these two features – proliferative stem-like CD8⁺ T cells and a less diverse reservoir – produced the strongest association with durable post-treatment control.

“We are excited to show that people who naturally suppress HIV after stopping treatment are able to do so because of this highly expansive and potent CD8⁺ T cell response, said corresponding author Gaurav Gaiha, MD, DPhil, associate professor of Medicine at Harvard Medical School and principal investigator at the Ragon Institute. “The reduced level of variability in the viral reservoir of these individuals also plays a key role, which we believe further supports therapeutic strategies of rational CD8⁺ T cell-based immune targeting.”

Charles Crain, the study’s first author and a current graduate student at UCSF, began working on this project 4 years ago. To him, these findings have both scientific and personal significance. 

“I started this project when I first joined the Gaiha lab as a research technician in 2022. It was a very meaningful way for me to grow and develop as a scientist while also contributing to research insights that I hope one day will lead to a cure for the millions of people living with HIV around the globe,” Crain said.

The findings have direct implications for HIV cure research. They suggest that vaccines or other therapies designed to boost these stem-like CD8⁺ T cell responses, particularly those aimed at constrained regions of the virus, could help a broader group of people achieve lasting remission. These approaches are currently being explored by the Gaiha Lab and a broader global network through clinical HIV T cell vaccine trials that leverage adenoviral vectors and mRNA.

The work builds on years of research from both the Gaiha lab, and the lab of Ragon founding director Bruce Walker, MD, into how the immune system targets and controls HIV. Ultimately, such findings may one day lead to a cure in which the immune system is able to keep HIV suppressed on its own, freeing people from a lifetime of daily medication regimens.