Highlights d SARS-CoV-2-infected RMs mimic signatures of inflammation seen in COVID-19 patients d Baricitinib suppresses production of pro-inflammatory cytokines in lung macrophages d Baricitinib limits recruitment of neutrophils to the lung and NETosis d Baricitinib preserves innate antiviral and SARS-CoV-2specific T cell responses

Summary Antiretroviral therapy (ART) suppresses viral replication in HIV-infected individuals, but does not eliminate the reservoir of latently infected cells. Recent work identified PD-1+ follicular helper T cells (Tfh) as an important cellular compartment for viral persistence. Here, using ART-treated, SIV-infected rhesus macaques, we show that CTLA-4+PD-1− memory CD4+ T cells, which share phenotypic markers with regulatory T cells, were enriched in SIV-DNA in blood, lymph nodes (LN), spleen, and gut, and contained replication-competent and infectious virus. In contrast to PD-1+ Tfh, SIV-enriched CTLA-4+PD-1− CD4+ T cells were found outside the B-cell follicle of the LN, predicted the size of the persistent viral reservoir during ART, and significantly increased their contribution to the SIV reservoir with prolonged ART-mediated viral suppression. We have shown that CTLA-4+PD-1− memory CD4+ T cells are a previously unrecognized component of the SIV and HIV reservoir that should be therapeutically targeted for a functional HIV-1 cure.

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While previous studies have shown that CD4+ T cells expressing CCR6 and CD161 are depleted from blood during HIV infection, the mechanisms underlying their loss remain unclear. In this study, we investigated how the homeostasis of CCR6+ and CD161+ CD4+ T cells contributes to SIV disease progression and the mechanisms responsible for their loss from circulation. By comparing SIV infection in rhesus macaques (RMs) and natural host sooty mangabeys (SMs), we found that the loss of CCR6+ and CD161+ CD4+ T cells from circulation is a distinguishing feature of progressive SIV infection in RMs. Furthermore, while viral infection critically contributes to the loss of CD161+CCR6-CD4+ T cells, a redistribution of CCR6+CD161− and CCR6+CD161+CD4+ T cells from the blood to the rectal mucosa is a chief mechanism for their loss during SIV infection. Finally, we provide evidence that the accumulation of CCR6+CD4+ T cells in the mucosa is damaging to the host by demonstrating their reduction from this site following initiation of antiretroviral therapy in SIV-infected RMs and their lack of accumulation in SIV-infected SMs. These data emphasize the importance of maintaining CCR6+ and CD161+ CD4+ T cell homeostasis, particularly in the mucosa, to prevent disease progression during pathogenic HIV/SIV infection.