Background
Elimination of latently HIV-infected cells remain the biggest challenge to reach a cure. Current immunotherapy approaches have focused on targeting the adaptive arm of the immune system, such as therapeutic vaccines and the passive transfer of broadly neutralizing antibodies. Recent studies showed that epigenetic reprogramming of innate myeloid cells triggered by adjuvants promoted protective interferon-induced antiviral immunity in vaccinees.
Methods
In this study, flow cytometry, cytokine array, and single-cell RNA-Seq/ATAC-Seq were conducted on SIV-infected, virologically suppressed rhesus macaques (RMs) treated with anti-IL-10 and anti-PD-1 antibodies (combo-treatment) before analytical treatment interruption (ATI).
Results
Ninety percent of the combo-treated RMs (9/10) successfully controlled viremia to levels lower than 10,000 cps/mL for at least 6 months post-analytical treatment interruption (ATI), and 40% of these RMs had a significant decrease in the cell-associated viral DNA quantities in lymph nodes (so-called CA-vDNAlo <100cps/10^6 CD4 T cells). Integrative analysis revealed that CA-VDNAlo RMs presented increased chromatin accessibility for target genes of IRF7/3 and STAT1, which resulted in significantly higher expression of IFN-stimulated antiviral machineries in myeloid cells and CD4+ T cells. On the other hand, combo-treated CA-vDNAhi RMs showed increased chromatin accessibility for the SMAD2/SMAD3, AP-1, and NFKB1 target genes and consequently higher expression of its downstream pathways (i.e. TGF-b signaling), resulting in higher SIV reservoir and higher susceptibility to infection during ATI. Of note, CA-vDNAhi RMs, presented significantly higher TGF-b plasma levels pre-ATI, and significantly higher frequencies of TGF-b+ Tregs prior to the immune intervention, which contributed to the increased downstream TGF-b signaling in these RMs. In vitro assays confirmed the detrimental impact of TGF-b on IFN-signaling, by blocking STAT1 phosphorylation, while the abrogation of such upstream signal, by using anti-TGFb antibody, unleashed the IFN-signaling and blocked HIV-infection. Signatures of the CA-vDNAlo RMs were observed in HIV elite controllers, who maintain undetectable levels of virus in the absence of ART and who present a small HIV reservoir size.
Conclusions
Overall, these results highlight the critical role of the interplay between TGF-b and IFN in the development of epigenetically regulated innate antiviral immune responses that can impact the viral reservoir.