Induction of Autophagy reduces IFN-I mediated Inflammation and restores anti-HIV-1 T Cell response in vivo

A hallmark of HIV-1 infection is chronic inflammation. Chronic immune activation drives the pathogenesis of HIV-1 infection, leading to loss of CD4+ T cells and exhaustion of antiviral cellular immunity. Previously, we demonstrated that persistent inflammation mediated by type I interferon (IFN-I) signaling drives T cell exhaustion. Combination of anti-retroviral therapy (ART) and IFN-I receptor blockade therapy led to accelerated viral suppression and reduced latent HIV-1 reservoirs, suggesting that targeting type I IFN signaling can be used as a therapeutic strategy to alleviate T cell exhaustion. However, as IFN-Is are key regulators for antiviral immunity, more specific interventions to fine-tune IFN-I signaling and chronic inflammation are needed. Autophagy is a homeostatic mechanism for disposal of damaged cellular organelles and elimination of intracellular pathogens, which is pivotal for cellular homeostasis, T cell development and function. Autophagy is also impaired during HIV-1 infection. Here we demonstrate that autophagy is directly linked to IFN-I signaling. Impairment of autophagy leads to accumulation of damaged mitochondria and spontaneous IFN-I signaling. Autophagy inducers reduce IFN-I signaling in activated macrophages and restore functions of exhausted anti-HIV-1 T cells in vitro. Importantly, autophagy inducer treatment in HIV-1 infected humanized bone marrow/liver/thymus (BLT) mice significantly reduced persistent IFN-I signaling and immune activation, restored exhausted antiviral T cell responses, and accelerated viral suppression by ART. Autophagy inducer treatment also led to reduced viral rebound after ART withdrawal. Taken together, our data suggest that therapeutically targeting autophagy could be used to treat persistent immune activation and improve immune control of HIV replication.