Background
Despite the cumulative expansion of the viral reservoir during untreated HIV-1 infection, it has been recently observed that the intact variants dated close to time of ART initiation predominate in the replicative-competent reservoir. This observation indicates that there is a critical window period immediately following ART initiation that significantly shapes the composition of the proviral reservoir. Still, deeper understanding of the dynamics of the latent reservoir and the factors modulating its composition is needed.
Methods
In this prospective study, we evaluated the decay dynamics of the different compartments of the HIV-1 reservoir in a group of 40 ART-naive individuals initiating dolutegravir-based regimens as part of the DUALITY study (Eudra-CT number 2019-002733-10). All participants were male, with most identifying as men who have sex with men (88.6%), and the median age was 31 years [IQR=23-35]. After starting ART, blood sampling was performed at baseline, at weeks 1, 2 and 4, and at months 3, 6 and 12. We quantified proviral DNA in peripheral CD4+ T cells by ddPCR. The inducible reservoir was measured by the VIP-SPOT assay. Reservoir decay was fitted to 2-phase biexponential decay dynamics using nonlinear mixed effects models.
Results
By the first week after ART initiation viral load had decreased by 2 logs, and beyond week 12, all participants remained virally suppressed except for a single blip in one individual. Over the first year on ART, both total and intact proviruses exhibited a similar overall decrease, representing the 81.6% and 83.7% reduction from the initial pool, respectively. This contrasts with the massive depletion of 96.6% of cells containing inducible proviruses. Furthermore, the half-life of the inducible reservoir after ART initiation was 2.6 days (95%CI=2.2-3.1 days), while the decay of the proviral reservoir was much slower, with a half-life of 5.1 weeks (95%CI=4.2-6.6).
Conclusions
Our findings demonstrate a rapid and specific clearance of cells harboring inducible proviruses within the first days after ART initiation. During this period, the interplay of opposing factors such as the expansion of CD4+ T cells and the restoration of host immune status collectively influences the composition of the long-lived HIV-1 reservoir. These findings support the idea that interventions focused on enhancing CTL responses or modulating viral latency may yield more significant benefits if implemented during this specific timeframe or just before ART initiation.
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