Background
HIV persistence during antiretroviral therapy (ART) is sustained by immunoregulatory pathways that suppress antiviral responses. IL-10 has been linked to reservoir size and shown to inhibit interferon stimulated genes (ISG). In SIV-infected rhesus macaques (RMs), anti-IL-10 alone (aIL10) led to partial control of viremia after treatment interruption, highlighting IL-10 as a regulator of reservoir persistence.
Methods
DOGMA-seq data (scRNA-seq, scATAC-seq, surface proteins and HIV viral DNA and RNA (vDNA, vRNA)) in memory CD4⁺ T cells of ART-suppressed people with HIV (PWH) were analyzed to assess the gene signatures of vDNA+ cells. In addition, SIV-infected RMs treated with aIL-10 vs control group were compared for their vRNA and vDNA levels in lymph nodes (LNs); scRNA-seq and scATAC-seq was also performed in LNs. Functional validation was performed in PBMCs by pharmacologic inhibition of the SWI/SNF remodeling downstream of IL-10/STAT3 signaling.
Results
Using DOGMA-seq we identified: 1) a cluster of HIV-DNA⁺ cells that showed elevated expression and accessibility of IL-10/STAT3–regulated genes i.e. the SWI/SNF chromatin remodeler SMARCA4, and of the epigenetic repressors HDAC4/7, consistent with enhanced chromatin silencing downstream of IL-10 signaling. Conversely, the IFNG locus in HIV-DNA⁺ cells showed repressed chromatin accessibility; 2) in HIV-DNA⁻ cells the IFNG locus remained accessible and transcriptionally active, with enrichment of EOMES and IRF motifs, supporting an active antiviral transcriptional profile in contrast to the immunoregulatory state of HIV-DNA⁺ cells. 3) In SIV-infected, ART-suppressed RM, aIL-10 treatment led to partial virologic control after ATI, with 4 of 9 animals within the aIL-10 arm showing significantly reduced plasma viremia and viral DNA compared to controls and to non-responders (p = 0.009). 4) Multiome profiling of LNs showed that aIL-10 enhanced chromatin accessibility at ISG loci (MX1, OASL, IRF9) in monocytes and CD4 T cells while concomitantly downregulating IL-10–associated chromatin remodelers, including SMARCA4. 5) Pharmacologic SMARCA inhibition in CD4 + T cells disrupted SWI/SNF activity and enhanced IFNβ-induced IRF1 expression, restoring antiviral ISG activation.
Conclusions
Our findings identify an IL-10/STAT3-dependent niche that promotes HIV reservoir survival while suppressing ISGs through SWI/SNF remodeling. Targeting IL-10 signaling may reactivate the virus in latently infected cells leading to their clearance.
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