HIV Stays Controlled in These Individuals Even After They Stop Treatment. Understanding Why Could Provide Clues to a ‘Functional Cure'

HIV post-treatment controllers (PTCs) are people with HIV who for reasons that are not completely understand are able to keep the virus under control even after stopping antiretroviral therapy.

Some HIV experts believe that studying PTCs could yield important insights into HIV and how the immune system responds to the virus that could point the way to functional cure.

Behzad Etemad, Ph.D., of Harvard-affiliated Brigham and Women's Hopsital led a study of 22 HIV "post-treatment-controllers," or PTCs. Even after they quit antiretroviral therapy, their HIV infections stayed in check.

Behzad Etemad, Ph.D., a researcher at Harvard-affiliated Brigham and Women’s Hospital in Boston and a team of 27 other researchers, many of them also at Harvard, reported the results of study of 22 PTCs recently in theProceedings of the National Academy of Sciences (PNAS). 

Jonathan Li, M.D., M.M.Sc.

Jonathan Z. Li, M.D., M.M.Sc., an infectious disease physician-scientist at the Brigham and Women’s Hospital and the corresponding author, notes that understanding how PTCs can maintain viral control without ART might help predict which patients can safely stop ART and provide insights into the design of new therapies for sustained ART-free HIV remission.

“The search for an HIV cure is one of the highest priorities in the field,” Li said “HIV post-treatment controllers are a rare group of individuals who can manifest natural control of HIV after stopping antiretroviral therapy. The existence of these individuals show that HIV remission is an achievable goal. However, the characteristics and mechanisms behind their ability to control HIV remains elusive.”

In the study, the researchers looked at PTCs from eight AIDS clinical trials group analytical treatment interruption studies. These 22 individuals were able to maintain HIV control (viral load <400 copies) for at least 24 weeks, with a median duration of control of about two years. Li and his colleagues compared them to a group of 37 “noncontrollers.”

“There were no significant differences in demographics or frequency of protective and susceptible human leukocyte antigen alleles between PTCs and post-treatment noncontrollers,” Li said. “Unlike noncontrollers, PTCs demonstrated a stable HIV reservoir measured by cell-associated RNA and intact proviral DNA assay during analytical treatment interruption.”

What’s more, immunologically, PTCs demonstrated significantly lower CD4+ and CD8+ T cell activation, lower CD4+ T cell exhaustion, and more robust Gag-specific CD4+ T cell responses and natural killer (NK) cell responses.

By using sparse partial least squares discriminant analysis, the study authors identified a set of features enriched in PTCs, including a higher CD4+ T cell percentage and CD4+/CD8+ ratio, more functional NK cells, and a lower CD4+ T cell exhaustion level. These results, Li notes, provide insights into the key viral reservoir features and immunological profiles for HIV PTCs and have implications for future studies evaluating interventions to achieve an HIV functional cure.

“Remarkably, we found that post-treatment controllers could maintain suppression of the HIV reservoir size and expression over a prolonged period of time,” Li said. “They were able to do this without significantly increased inflammation or immune activation. We found a number of immune features that were enriched in post-treatment controllers, including robust HIV-specific CD4 T cell activity and natural killer cell responses.”

The study revealed several important viro-immunological features associated with post-treatment control, and the researchers believe their findings can shed light on future HIV cure studies.

“We hope that these findings will provide researchers with a roadmap of how HIV remission can be achieved,” Li said.