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

Abstract

Abstract 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 immune exhaustion. Previously, we demonstrated that persistent type I interferon (IFN-I) signaling drives T cell exhaustion during chronic HIV infection and combined anti-retroviral therapy (ART) and IFN-I receptor blockade could lead to reduced inflammation, accelerated viral suppression and HIV reservoir. 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 is a promising approach for treating persistent immune activation and improve immune control of HIV replication. This work was funded by NIAID 1R21AI140866 (to Zhen), NIDA R01DA-52841 (to Zhen), NIAID R2120200174 (PIs: Xie&Zhen), NCI 1R01CA239261-01 (to Kitchen), NIH Grants NIH Grants P30AI28697 (the UCLA CFAR Virology Core, Gene and Cell Therapy Core, and Humanized Mouse Core), U19AI149504(PIs: Kitchen & Chen), CIRM DISC2-10748, UPLIFT: UCLA Postdocs’ Longitudinal Investment in Faculty (Award # K12 GM106996) (to Carrillo), R01 AG052340 (to Jamieson). This work was also supported by the UCLA AIDS Institute, the James B. Pendleton Charitable Trust, and the McCarthy Family Foundation. We would also like to thank Drs. Romas Geleziunas and Jeff Murry and the people at Gilead for providing the antiretroviral drugs used in this study.