TGF-β mediates epigenetic control of innate antiviral responses and SIV reservoir size.

Immune interventions toward an HIV cure have focused on rejuvenating adaptive immune responses. Herein we provide a framework that features epigenetic programming of myeloid and CD4+ T cells as a major mechanism that promotes decay of the HIV reservoir. Coordinate regulation of gene expression and chromatin accessibility of pathways of innate antiviral immunity was associated with decay of cell-associated viral DNA (CA-vDNA) following analytical treatment interruption in simian immunodeficiency virus-infected rhesus macaques (RMs) treated with anti-IL-10 and anti-PD-1. TGF-β/SMAD signaling in a subset of combo-treated CA-vDNAhi RMs, suppressed this antiviral activity through histone deacetylases, reducing chromatin accessibility of interferon regulatory factors (IRFs) and STATs. Addition of HDAC inhibitors in vitro restored antiviral response in the presence of TGF-β. Induction of IL-6 in CA-vDNAlo RMs amplified the antiviral network through IRF9. We identified an overlapping molecular cascade in HIV elite controllers, who maintain small HIV reservoirs without antiviral treatment. These data provide insights into strategies for HIV cure interventions.