A5345 Provides Insights into Predictors of HIV Rebound  

HIV cure is a crucial area of HIV research and one which ACTG is committed to investigating. While current ART can manage HIV very well, it does not cure it and people living with HIV must take it for the rest of their lives to suppress viral replication and protect their immune systems. Even when taking ART, people living with HIV have latent HIV reservoirs, which are groups of immune systems cells that carry HIV in a dormant state (i.e., the virus is not able to actively reproduce to create new copies). When people stop taking ART, the virus usually starts multiplying again, rapidly increasing the amount of HIV in a person’s body. As such, analytic treatment interruptions (ATIs; closely monitored treatment pauses) play a crucial role in HIV cure studies as they are currently the only way to know if dormant virus is still hiding in the body. Study A5345 was designed to identify surrogate factors that can predict the timing when HIV may rebound. The hope is that, by identifying these factors, researchers will be able to gauge the effectiveness of treatments without having to interrupt HIV treatment. This approach could accelerate the development of safer and more effective HIV cure strategies.


In this study, which was recently published in the journal JCI Insight, participants had been virally suppressed on ART for at least two years; 33 participants began taking ART during chronic HIV infection while 12 began taking it early after acquiring HIV. All participants interrupted ART and were closely monitored for virus in the blood. Participants restarted ART if they had two HIV viral loads of at least 1,000 copies/mL after ATI. As expected, participants who began treatment during early infection had smaller and less active HIV reservoirs, compared with those who began treatment when they had chronic infection.


Overall, greater HIV specific CD8 T cells response was associated with lower intact proviral DNA. Interestingly, predictors of viral rebound were different across treatment groups. The strongest reservoir predictor of time to HIV rebound was the level of residual viremia in plasma in early-treated participants, while intact DNA level was the strongest predictor in chronic-treated individuals. Researchers also identified distinct sets of pre-ATI viral, immune, and inflammatory markers that differentiated participants who had rapid versus slow rebound; these also differed between treatment groups.


These results demonstrate that starting HIV treatment as early as possible resulted in less active virus that was able to reproduce in the HIV reservoir. They provide insights into the complex interplay of viral, immunologic, and inflammatory predictors of viral rebound and demonstrate that the timing of ART initiation modifies the features of rapid and slow viral rebound. This information help guide new studies looking at HIV cure and lowering the amount of active virus in the reservoir.


JCI Insight. 2024;9(3):e173864.https://doi.org/10.1172/jci.insight.173864.