TGF-b mediates epigenetic control of innate antiviral responses and SIV/HIV reservoir size 4405

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Abstract Description Immunotherapeutic approaches to eliminate latently HIV-infected cells are focused on the adaptive immune system. Herein we provide mechanistic evidence for a molecular cascade highlighted by epigenetic reprogramming of innate myeloid cells mediated by specific transcription factors (IRF-3, IRF-7, STAT-1, and C/EBPβ). This cascade promotes the development of innate antiviral immunity that triggers viral load control and viral DNA (vDNA) decay post-ATI in SIV-infected rhesus macaques (RMs) treated with anti-IL-10 and anti-PD-1. The balance between the antiviral signaling driven by IRFs, STATs, and C/EBPβ and the pro-inflammatory response mediated by AP-1 triggered the decay of vDNA levels in lymph nodes. TGF-β/SMAD signaling suppressed this antiviral activity through HDAC11, which blocked the chromatin accessibility of IRFs/STATs and impeded their antiviral functions. HDAC inhibitors restored this antiviral response in the presence of TGF-β. IL-6 induction, a target of C/EBPβ, amplified the antiviral network through IRF9, a TF upstream of IRF7, a feature specific of RMs with lower vDNA levels. HIV elite controllers, who maintain undetectable viremia and small viral reservoirs without treatment showed similar molecular cascade. In summary, our data highlights the importance of epigenetic regulation in shaping innate antiviral immune response that controls viral rebound and reduces the viral reservoir, providing insight into potential strategies for HIV cure interventions. Funding Sources R37AI141258 P01AI178376 UM1AI164561 Topic Categories Viral Immunology (VIR)

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