Autophagy interaction with herpes simplex virus type-1 infection

Abstract

More than 50% of the U.S. population is infected with herpes simplex virus type-I (HSV-1) and global infectious estimates are nearly 90%. HSV-1 is normally seen as a harmless virus but debilitating diseases can arise, including encephalitis and ocular diseases. HSV-1 is unique in that it can undermine host defenses and establish lifelong infection in neurons. Viral reactivation from latency may allow HSV-1 to lay siege to the brain (Herpes encephalitis). Recent advances maintain that HSV-1 proteins act to suppress and/or control the lysosome-dependent degradation pathway of macroautophagy (hereafter autophagy) and consequently, in neurons, may be coupled with the advancement of HSV-1-associated pathogenesis. Furthermore, increasing evidence suggests that HSV-1 infection may constitute a gradual risk factor for neurodegenerative disorders. The relationship between HSV-1 infection and autophagy manipulation combined with neuropathogenesis may be intimately intertwined demanding further investigation.

Keywords: ICP34.5; autophagy; herpes simplex virus; immune evasion; neurodegeneration.

Figure 1.

The autophagy pathway and its interaction with HSV-1. Upon HSV-1 infection, autophagy is stimulated through the activation of an IFN-inducible EIF2AK2/PKR-EIF2S1/eIF2α signaling cascade, which shuts off host protein synthesis and concomitantly turns on autophagy by hitherto unclear mechanisms (indicated by the question mark). Autophagy induction sequesters cytoplasmic contents, forming autophagosomes characterized by the LC3-I → LC3-II conversion and ATG12–ATG5-ATG16L1 supercomplex association. As lysosomes and/or endosomes fuse, many factors contribute to the formation of the autolysosome, enabling degradation of contents by hydrolytic enzymes. Digested materials can be recycled back into the cytosol for use in energy production, protein manufacturing or be delivered to antigen presentation pathways in response to infection. As such, autophagy is shown to be able to directly capture the neuroattenuated ICP34.5-mutant HSV-1 virions or viral components, delivering them for lysosomal degradation and/or for the antigen presentation of viral peptides to the MHC-I/-II pathway for adaptive immune activation. To counteract the antiviral role of EIF2AK2 and cellular autophagy, viral protein Us11 prevents EIF2AK2-mediated EIF2S1 phosphorylation. Interestingly, ICP34.5 acts to reverse phosphorylated EIF2S1 by recruiting of host phosphatase PPP1CA/PP1α. In addition, ICP34.5 restricts autophagic initiation and maturation by targeting BECN1, preventing BECN1 autophagy complex formation. ICP34.5 also engages TBK1 to inhibit TBK1-mediated antiviral signaling, and may also prevent autophagic cargo recruitment through TBK1-mediated SQSTM1 phosphorylation. Although the response of nuclear envelope-derived autophagosomes (NEDA) can be triggered by ICP34.5-associated active protein translation or independently by expression of abundant viral late proteins (e.g., gH [glycoprotein H]), ICP34.5 can restrict the NEDA maturation that engages in viral antigen presentation. The interplay between the herpes pathogen and its host cell reflects a constant battle for control. RUBCN, RUN domain and cysteine-rich domain containing, Beclin 1-interacting protein; VPS, vacuolar protein sorting.