Differential decay of intact and defective proviral DNA in HIV-1–infected individuals on suppressive antiretroviral therapy

Understanding the dynamics of the latent HIV-1 reservoir is essential for developing curative strategies. While antiretroviral therapy (ART) effectively suppresses viral replication, it does not eliminate the virus. This study aimed to characterize the long-term decay kinetics of intact (replication-competent) versus defective (replication-incompetent) HIV-1 proviral DNA in individuals on long-term suppressive ART.

The researchers analyzed longitudinal peripheral blood mononuclear cell (PBMC) samples from 81 HIV-infected individuals using the Intact Proviral DNA Assay (IPDA). This assay uses droplet digital PCR to distinguish between intact and defective proviruses by simultaneously targeting the packaging signal and env regions. The team employed linear spline models with a knot at seven years to estimate the rates of change and identify factors, such as CD4+ T cell nadir, that influence reservoir decay.

The study revealed that the intact HIV-1 reservoir is not static but decays at different rates over time. During the first seven years of suppressive ART, intact proviruses declined at a rate of 15.7% per year, corresponding to a half-life of approximately 4.0 years. After seven years, this decay slowed significantly to 3.6% per year, with an estimated half-life of 18.7 years. In contrast, defective proviruses showed a slower overall decline. Furthermore, individuals with higher CD4+ T cell nadirs experienced a faster rate of decay for intact proviruses, suggesting that immune status at the time of treatment initiation plays a critical role in reservoir dynamics.

These findings demonstrate that the replication-competent reservoir has distinct biological properties compared to the defective pool. The observed slowing of decay after seven years suggests that ART alone is unlikely to eradicate the virus, as it would take over two centuries to achieve a 4-log reduction in intact proviral DNA. The results highlight the necessity of developing novel therapeutic interventions to target the persistent reservoir and suggest that the IPDA is a valuable tool for monitoring the efficacy of such treatments.