IFNa-blockade during ART-treated SIV infection lowers tissue vDNA, rescues immune function, and improves overall health

Type I interferons (TI-IFNs) drive immune effector functions during acute viral infections and regulate cell cycling and systemic metabolism. That said, chronic TI-IFN signaling in the context of antiretroviral therapy (ART)-treated HIV infection also facilitates viral persistence, in part by promoting immunosuppressive responses and CD8 T cell exhaustion. To determine whether inhibition of IFN-a might provide benefit in the setting of chronic, ART-treated SIV infection of rhesus macaques, we administered an anti-IFN-a antibody followed by an analytical treatment interruption (ATI). IFN-a blockade was well-tolerated and associated with lower expression of TI-IFN inducible genes (including those that are antiviral) and reduced tissue viral DNA (vDNA). The reduction in vDNA was further accompanied by higher innate pro-inflammatory plasma cytokines, expression of monocyte activation genes, IL-12 induced effector CD8+ T cell genes, increased heme/metabolic activity, and lower plasma TGF-ß levels. Upon ATI, SIV-infected, ART-suppressed nonhuman primates (NHPs) treated with anti-IFN-a displayed lower levels of weight loss and improved erythroid function relative to untreated controls. Overall, these data demonstrate that IFN-a blockade during ART-treated SIV infection is both safe and associated with the induction of immune/erythroid pathways that reduce viral persistence during ART while mitigating the weight loss and anemia that typically ensue following ART interruption.

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