The role of bystander cell autophagy in HIV-1 infection

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Efficient spread of human immunodeficiency virus 1 (HIV-1) is controlled by the availability and anti-viral state of non-infected bystander cells. The anti-viral state is defined by the activity of innate and intrinsic immune antiviral effector pathways, such as autophagy. Autophagy is an auto-digestive process targeting cellular proteins or viral components for destruction. Like other immune pathways, autophagy is induced upon infection with HIV-1. However, dissection of the response revealed that autophagy levels in HIV-1 infected CD4+ T cells are surprisingly low. In contrast, in non-infected bystander T cells high levels of autophagy are induced. Our data further showed that bystander autophagy is induced by a soluble factor released from HIV-1 infected T cells. We intend to determine how bystander cell autophagy induction in HIV-1 infection works on a molecular level. To this end, we will determine cellular sensing pathways and viral determinants in infected cells that induce the release of the unknown autophagy-inducing factor. Furthermore, we will determine the identity of the signalling factor on which cell types it induces autophagy and which cell types release it after infection. Finally, we will use advanced CRISPR approaches to define determinants of autophagy upregulation in bystander cells. To understand the impact of bystander autophagy, we will determine its consequences on HIV 1 infection of T cells. Our preliminary data show that cells with high autophagic flux are less permissive for HIV-1, thus viral spread is limited. However, activation of autophagy may eventually come at a cost. Cell death induced by excessive autophagy may contribute to depletion of bystander T cells, a hallmark of AIDS. Taken together, this project will yield novel insights into the pathogenesis of AIDS, interplay of HIV-1 with autophagy and explore regulatory features of cell intrinsic defenses. We aim to establish the novel concept of paracrine autophagy activation and define key factors involved. Understanding the impact and regulation of bystander cell autophagy during HIV-1 infection will allow us to design strategies to fine-tune anti-viral cell-intrinsic immunity. Since autophagy is a broadly active anti-microbial pathway these strategies may be the basis of future therapeutic or preventive approaches targeting not only HIV-1 but also other pathogens. Furthermore, these fundamental insights into autophagy may be relevant for diseases where autophagy is dysregulated, among them cancer and neuropathologies.This project will benefit from and complement the SPP by introducing autophagy, while being firmly rooted in sensing and restriction of HIV-1. I believe that concepts of this proposal will spark new impulses for other projects and thus nurture new collaborations within the SPP.