Divergent roles of autophagy in virus infection

Abstract

Viruses have played an important role in human evolution and have evolved diverse strategies to co-exist with their hosts. As obligate intracellular pathogens, viruses exploit and manipulate different host cell processes, including cellular trafficking, metabolism and immunity-related functions, for their own survival. In this article, we review evidence for how autophagy, a highly conserved cellular degradative pathway, serves either as an antiviral defense mechanism or, alternatively, as a pro-viral process during virus infection. Furthermore, we highlight recent reports concerning the role of selective autophagy in virus infection and how viruses manipulate autophagy to evade lysosomal capture and degradation.

Figure 1

Schematic representation of autophagy. The first step in the initiation of mammalian autophagy is the formation of the phagophore, followed by subsequent steps, which include elongation and expansion of the phagophore, closure and completion of a double-membrane autophagosome (which engulfs a portion of the cytoplasm), autophagosome maturation via docking and fusion with endosomal compartments (to form a hybrid vesicular product known as an amphisome) and/or with a lysosome (to form the autolysosome). The inner autophagosomal membrane and cargo is degraded by acid hydrolases inside the autolysosome, and recycling of the resulting macromolecules is mediated via permeases. The molecular machinery regulating autophagy is also depicted. ULK1 and ULK2 complexes that are crucial for induction of autophagy, PI3Kinase-Beclin1 complexes, are required for autophagosome formation, the delivery of membranes to the forming autophagosome is mediated by mammalian Atg9 (mAtg9) and two conjugation systems: LC3-II and Atg12–Atg5–Atg16L complex, which are required during elongation and expansion of the phagophore.

Figure 2

Viral manipulation of autophagy. Viruses can either induce (green arrows) or inhibit the autophagy pathway (red studded lines). Viral induction of autophagy can be achieved during viral entry via interaction with cell surface receptors, via interaction with stress sensors or during viral replication. Viruses also inhibit autophagy at early or late stages of the pathway, during initiation or maturation, respectively. For further details, see the legend for Figure 1. Abbreviations: HIV-1 (human immunodeficiency virus-1); CXCR4 (C-X-C chemokine receptor type 4); VSV (vesicular stomatitis virus); TLR7 (Toll-like receptor 7); CD46 (cluster of differentiation 46); GOPC (Golgi-associated PDZ and coiled-coil motif-containing protein); KSHV (Kaposi’s sarcoma herpesvirus); MHV68 (murine γ-herpesvirus 68); HSV-1 (herpes simplex virus-1); FluAV (influenza A virus); CVB3 (coxsackievirus B3); DENV (dengue virus); HCV (Hepatitis C virus); HBV (Hepatitis B virus); VZV (varicella-zoster virus) ER (endoplasmic reticulum).

Figure 3

Antiviral functions of autophagy during virus infection. Autophagy can restrict viral replication via different mechanisms. Autophagy selectively transfers viral nucleic acids to endosomal compartments to stimulate innate immune responses via TLRs. Furthermore, autophagy can selectively target viral components and degrade them in lysosomes. Lastly, autophagy mediates the delivery of viral antigens to MHC-I and -II complexes to allow antigen presentation.

Figure 4

Proviral functions of autophagy. Autophagy is known to exert diverse proviral functions during viral infection. Autophagosomes have been proposed provide a membrane platform for viral replication complexes or to mediate virus assembly and release. Furthermore, viruses can trigger selective autophagy to degrade either lipids (lipid droplets) for energy production during viral replication or to subvert immune responses by selectively degrading key regulatory molecules. The mechanistic details related to proviral functions of autophagy are discussed in the text.