TGF-ß controls epigenetic re-programing of IFN-antiviral trained immunity and impairs virologic control in SIV-infected rhesus macaques [scMultiome]

Current immunotherapeutic approaches to eliminate latently HIV-infected cells have focused on targeting the adaptive arm of the immune system using vaccines and passive transfer of broadly neutralizing antibodies (bNAbs). Epigenetic reprogramming of innate myeloid cells triggered by adjuvants was recently shown to promote a state of interferon (IFN)-induced antiviral immunity and resistance to heterologous viral infections. Herein, flow cytometry, bulk and single-cell RNA-Seq/ATAC-Seq were performed on samples from a cohort of SIV-infected, virologically suppressed rhesus macaques (RMs) treated with anti-IL-10 and anti-PD-1 monoclonal antibodies (combo treatment) prior to analytical treatment interruption (ATI). These experiments revealed that combo treatment led to selective changes in chromatin accessibility, expression of IRF7/3 and STAT1, and expression of IFN-stimulated antiviral genes in myeloid cells and CD4+ T cells. These RMs showed a stringent and prolonged control of SIV viral rebound following ATI and a decay in levels of cell-associated viral DNA (CA-vDNA) in lymph nodes. These RMs showed reduced chromatin accessibility for the SMAD2/SMAD3, AP-1, and NFKB1 loci and lower expression of TGF-b and SMADs target genes. This signature is consistent with that observed in HIV elite controllers, who maintain undetectable levels of virus in the absence of ART and whose HIV reservoir size is small. These results highlight the critical role of the interplay between TGF-b and IFN in epigenetically regulated innate antiviral immune responses that can impact the viral reservoir. Overall design: Twenty-eight rhesus macaques were infected intravenously with SIVmac239. After 14 months on antiretroviral therapy (ART), RMs were randomized into 3 groups: 8 RMs received vehicle and served as controls; 10 RMs received deimmunized aIL-10, and 10 RMs received deimmunized aIL-10 and deimmunized aPD-1 (combo group). Combo-treated animals were dichotomized as CA-vDNAlo (n = 4) and CA-vDNAhi (n = 6) based on the size of the SIV reservoir 24 weeks post-ATI (<2 log10 and >2 log10 CA-vDNA copies per 106 CD4+ T cells, respectively)