Varicella zoster virus encodes a viral decoy RHIM to inhibit cell death

Abstract

Author Summary: 43 44 Rip homotypic interaction motifs (RHIMs) are found in host proteins that can signal 45 for programmed cell death and in viral proteins that can prevent it. Complexes 46 stabilized by intermolecular interactions involving RHIMs have a fibrillar amyloid 47 how a decoy amyloid strategy is employed by pathogens to circumvent the host 55 response. 56 57 58 Viruses have evolved a diverse range of strategies to evade host intrinsic, innate and 59 adaptive immune responses. Members of the Herpesviridae family, Herpes simplex 60 virus (HSV) -1 and human and murine cytomegalovirus (HCMV/MCMV), are 61 masters at manipulating host cell death pathways such as apoptosis and necroptosis, in 62 order to successfully spread and establish latency (1-3). Although Varicella zoster 63 virus (VZV) causes a significant health burden (4-6), the mechanisms employed by 64 VZV to undermine host responses have not been fully elucidated. Primary infection 65with VZV leads to varicella, commonly known as chickenpox. During this infection 66 the virus establishes latency within sensory neurons, and when VZV-specific T cell 67 immunity wanes, the virus can reactivate to result in herpes zoster (shingles) (7). 68Complications arising from VZV reactivation include protracted pain termed post-69 herpetic neuralgia, encephalitis and VZV vasculopathy (reviewed in 8). 70VZV is a highly cell-associated virus and does not release cell-free virions into 71 culture (9), necessitating cell-associated propagation of the virus in vitro. VZV is also 72 highly species-specific, not progressing to productive infection in cells of non-human 73 origin (10). Therefore no animal model exists which re-capitulates the full spectrum 74 of VZV disease. Combined, these properties of VZV have largely hampered the 75 characterization of VZV pathogenesis. 76