IL-10 and Coordinated Cytokine Responses Predict Rapid HIV Reservoir Decay in Acute Treated HIV Infection

Background: The HIV reservoir is established within days of infection and persists despite antiretroviral therapy (ART). However, data describing early reservoir decay dynamics and the host immune responses associated with this process remain limited. Methods: We analyzed more than 500 longitudinal blood samples from 67 individuals treated during acute HIV infection. Plasma cytokines and HIV reservoir size (intact and defective DNA) were quantified. Associations between immune markers and reservoir decay following ART initiation were assessed using unsupervised clustering, mixed-effects linear spline models, and nonlinear modeling. Results: Higher levels of IFN-{gamma}, IL-10, IL-18, and TNF- during weeks 24-52 of ART were associated with significantly faster decay of both intact and defective HIV DNA. These relationships were independent of ART initiation timing (days since infection), baseline viremia, initial CD4+ T cell count, and longitudinal CD4:CD8 ratio. Among these cytokines, IL-10 demonstrated the strongest association with accelerated reservoir decay, despite prior evidence linking it to larger reservoirs in SIV models. Discussion: These findings highlight the pleiotropic and stage-dependent roles of cytokines across acute to later stages of HIV, suggesting that a coordinated balance between immune activation and regulation of inflammation may promote early HIV reservoir decay.