title: Interaction of ICP34.5 with Beclin 1 modulates herpes simplex virus type 1 pathogenesis through control of CD4+ T-cell responses.
abstract: Autophagy is an important component of host innate and adaptive immunity to viruses. It is critical for the degradation of intracellular pathogens and for promoting antigen presentation. Herpes simplex virus type 1 (HSV-1) infection induces an autophagy response, but this response is antagonized by the HSV-1 neurovirulence gene product, ICP34.5. This is due, in part, to its interaction with the essential autophagy protein Beclin 1 (Atg6) via the Beclin-binding domain (BBD) of ICP34.5. Using a recombinant virus lacking the BBD, we examined pathogenesis and immune responses using mouse models of infection. The BBD-deficient virus (Delta68H) replicated equivalently to its marker-rescued counterpart (Delta68HR) at early times but was cleared more rapidly than Delta68HR from all tissues at late times following corneal infection. In addition, the infection of the cornea with Delta68H induced less ocular disease than Delta68HR. These results suggested that Delta68H was attenuated due to its failure to control adaptive rather than innate immunity. In support of this idea, Delta68H stimulated a significantly stronger CD4(+) T-cell-mediated delayed-type hypersensitivity response and resulted in significantly more production of gamma interferon and interleukin-2 from HSV-specific CD4(+) T cells than Delta68HR. Taken together, these data suggest a role for the BBD of ICP34.5 in precluding autophagy-mediated class II antigen presentation, thereby enhancing the virulence and pathogenesis of HSV-1.
authors.affiliation: Department of Microbiology and Immunology, Dartmouth-Hitchcock Medical Center, Lebanon, NH 03756, USA. David.A.Leib@Dartmouth.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Leib
authors.forename: Diane E
authors.initials: DE
authors.lastname: Alexander
authors.forename: Douglas
authors.initials: D
authors.lastname: Cox
authors.forename: Jiyi
authors.initials: J
authors.lastname: Yin
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Ferguson
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002522:Chlorocebus aethiops; D018259:Herpesvirus 1, Human / Q000235:genetics / Q000276:immunology / Q000472:pathogenicity*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054730:Protein Interaction Domains and Motifs; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D017384:Sequence Deletion; D014709:Vero Cells; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D011994:Recombinant Proteins; D014764:Viral Proteins; C066469:gamma 34.5 protein, Human herpesvirus 1