Background:
The HIV reservoir largely consists of ‘defective’ virus, but the elimination of the ‘intact’ (replication-competent) reservoir is a major focus of HIV eradication strategies. There are limited data describing reservoir decay rates during the first few months of acute-treated HIV, nor the host immune responses that drive reservoir decay. We quantified plasma cytokine levels from >500 longitudinal samples from the UCSF Treat Acute HIV cohort to determine immunologic pathways that predict reservoir decay in people with HIV (PWH).
Methods:
Individuals diagnosed with acute (<100 days) HIV were enrolled between 2015-2020, immediately initiated on ART (tenofovir/emtricitabine+dolutegravir), and followed monthly for the first 24 weeks of ART initiation. Frequencies of intact vs. defective provirus were quantified using the IPDA®. High-sensitivity multiplex plasma cytokine assays were performed from cryopreserved plasma samples (MesoScale Diagnostics). Multivariate nonlinear general additive models were adjusted for false discovery rate (FDR) using the Benjamini-Hochberg method.
Results:
Among 67 PWH diagnosed <100 days from HIV acquisition, we observed an initial rapid (<8 weeks) decay, followed by second slower (8-24 weeks) decay of both intact and defective HIV proviral DNA during the first 24 weeks of ART. Among 20 plasma cytokines assayed across these same longitudinal timepoints (weeks 0, 2, 4, 8, 12, 16, 20, 24), IL-10 and type I interferons (IFN-β) significantly predicted accelerated reservoir decay even after adjustment for initial CD4+ T cell count, pre-ART viral load, age, and timing of ART initiation. IL-10 was significantly associated with faster decay rates for intact, but not defective virus, during both phases of decay (5.74% and 1.32% increase in decay rate/week per unit-increase in IL-10, respectively). IFN-β was significantly associated with faster decay rates during the second decay phase (0.89% intact and 1.55% defective HIV DNA).
Conclusions:
Individuals with higher plasma IL-10 and type I IFN expression during the first 24 weeks of ART demonstrated accelerated HIV reservoir decay. These cytokines are well known to exert variable effects on the host immune response depending on stage of disease (e.g., favorable during acute but detrimental during chronic infection). Our findings add insight into the complexity of these pleiotropic cytokines and highlight the need for potential stage-specific targeting of these cytokines in future HIV cure strategies.
