Autophagy-Virus Interplay: From Cell Biology to Human Disease

Abstract

Autophagy is a highly conserved intracellular degradation process that targets protein aggregates and damaged organelles. Autophagy is also implicated in numerous viral infections, including human immunodeficiency virus-1 (HIV-1), influenza A (IAV) and herpes simplex virus-1 (HSV-1). Depending on the virus, autophagy can restrict or promote viral replication, and play key roles in modulating inflammation and cell survival. In this review, we consider examples of autophagy-virus interplay, highlighting the protective role of autophagy in human infections. We summarize recent discoveries and emerging themes illuminating autophagy's role in immunity and inflammation upon viral infection. Finally, we discuss future prospects and therapeutic implications, and potential caveats associated with using autophagy to control viral infections in humans.

Keywords: HIV-1; HSV-1; IAV; autophagy; inflammation; viral immunity.

FIGURE 1

(A) Autophagy is a regulated multi-step process that leads to cargo degradation. Autophagy can eliminate cargo such as virus and viral-derived antigens. It can be organized into 5 distinct steps beginning with (1) the initiation of phagophore formation which (2) nucleates around the intended cargo. The cargo can be selectively recruited by autophagy receptors such as p62, which can be regulated by TBK1. (3) The phagophore elongates and completes to form a structure termed autophagosome which then (4) fuses with nearby lysosomes carrying hydrolytic enzymes. This eventually leads to (5) the acidification and hence degradation of the contained cargo. (B) Autophagy plays an antiviral role in various human infections by modulating different aspects of the immune response. Autophagy facilitates viral clearance by recruiting selective autophagy receptors p62 and SMURF1 to target viral components to autophagosomes for lysosomal degradation. Reported targets include HSV-1, HIV-1 Tat protein, and the capsids of CHIKV and SV. Disruption of the targeting of viral proteins, such as CHIKV and SV capsids, may lead to their toxic accumulation and cause cell death. Autophagy also promotes pathogen recognition by aiding delivery of viral PAMPs, e.g., HIV-1 and IAV RNA genomes to cognate TLRs in endosomes, which results in enhanced production of antiviral cytokines. On the other hand, autophagy can prevent excessive inflammation by negatively regulating signaling pathways through Atg9a or Beclin-1, or by clearing mitochondria that are producing inflammatory-inducing signals such as reactive oxygen species (ROS). Autophagy supports amplification of inflammatory responses by regulating adaptive immune responses, through the processing and presentation of viral antigens, such as EBV EBNA1, IAV MP1, HIV-1/SIV gag and HSV-1 glycoprotein B, on MHC class I or II to T cells. Autophagy can also be induced in distant cells, i.e., in paracrine manner, which may confer protection to these cells as seen with multiple viral infections including CVB, HCV, and HSV-1.