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

TL;DR

This study shows how TGF-β affects the epigenetic control of antiviral responses in innate immune cells, influencing the size of the SIV reservoir in rhesus macaques.

Contribution

The paper identifies a novel molecular cascade involving TGF-β and epigenetic regulation that controls antiviral immunity and viral reservoirs.

Findings

TGF-β/SMAD signaling suppressed antiviral activity through HDAC11 in some treated rhesus macaques.

HDAC inhibitors restored antiviral responses in the presence of TGF-β in vitro.

A similar molecular cascade was observed in HIV elite controllers with low viral reservoirs.

Abstract

Immunotherapeutic approaches to eliminate latently HIV-infected cells are focused on the adaptive immune system. Herein we provide mechanistic evidence for a molecular cascade characterized by epigenetic reprogramming of innate myeloid cells and CD4 T cells. The coordinate regulation and gene expression mediated by transcription factors (TFs) IRF3, IRF7, STAT1 and C/EBPβ versus AP-1, promoted the development of innate antiviral immunity in these cells which was associated with control of viral load and decay of cell associated viral DNA (CA-vDNA) following analytical treatment interruption (ATI) in SIV-infected rhesus macaques (RMs) treated with anti-IL-10 and anti-PD-1. The prevalence of TGF-β/SMAD signaling in a subset of combo-treated RMs with high CA-vDNA (CA-vDNAhi) suppressed this antiviral activity through histone deacetylases, including HDAC11, as the latter reduced chromatin accessibility of IRFs and STATs and impeded their antiviral functions. The addition of HDAC inhibitors in vitro restored antiviral response in the presence of TGF-β. Induction of IL-6, a target gene of C/EBPβ, in CA-vDNAlo RMs, amplified the antiviral network through IRF9, a transcription factor upstream of IRF7. We identified a similar molecular cascade in HIV elite controllers, who maintain low to undetectable viremia and small viral reservoirs without treatment. These data highlight the importance of epigenetic regulation of the host in shaping innate antiviral immune responses that control viral rebound following ATI and reduce the viral reservoir, providing insight into potential strategies for HIV cure interventions.

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