title: Attenuation of the adaptive immune response in rhesus macaques infected with simian varicella virus lacking open reading frame 61.
abstract: Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus that causes chickenpox during primary infection and establishes latency in sensory ganglia. Infection of rhesus macaques (RM) with the homologous simian varicella virus (SVV) recapitulates hallmarks of VZV infection. We have shown that an antisense transcript of SVV open reading frame 61 (ORF61), a viral transactivator, was detected most frequently in latently infected RM sensory ganglia. In this study, we compared disease progression, viral replication, immune response, and the establishment of latency following intrabronchial infection with a recombinant SVV lacking ORF61 (SVVΔORF61) to those following infection with wild-type (WT) SVV. Varicella severity and viral latency within sensory ganglia were comparable in RMs infected with SVVΔORF61 and WT SVV. In contrast, viral loads, B and T cell responses, and plasma inflammatory cytokine levels were decreased in RMs infected with SVVΔORF61. To investigate the mechanisms underlying the reduced adaptive immune response, we compared acute SVV gene expression, frequency and proliferation of dendritic cell (DC) subsets, and the expression of innate antiviral genes in bronchoalveolar lavage (BAL) samples. The abundance of SVV transcripts in all kinetic classes was significantly decreased in RMs infected with SVVΔORF61. In addition, we detected a higher frequency and proliferation of plasmacytoid dendritic cells in BAL fluid at 3 days postinfection in RMs infected with SVVΔORF61, which was accompanied by a slight increase in type I interferon gene expression. Taken together, our data suggest that ORF61 plays an important role in orchestrating viral gene expression in vivo and interferes with the host antiviral interferon response.
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Portland, Oregon, USA.
authors.forename: Christine
authors.initials: C
authors.lastname: Meyer
authors.forename: Amelia
authors.initials: A
authors.lastname: Kerns
authors.forename: Kristen
authors.initials: K
authors.lastname: Haberthur
authors.forename: Jesse
authors.initials: J
authors.lastname: Dewane
authors.forename: Joshua
authors.initials: J
authors.lastname: Walker
authors.forename: Wayne
authors.initials: W
authors.lastname: Gray
authors.forename: Ilhem
authors.initials: I
authors.lastname: Messaoudi
mesh_terms: D056704:Adaptive Immunity; D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology / Q000821:virology; D002644:Chickenpox / Q000276:immunology / Q000473:pathology / Q000821:virology; D016207:Cytokines / Q000097:blood; D017950:Ganglia, Sensory / Q000821:virology; D017353:Gene Deletion; D014645:Herpesvirus 3, Human / Q000235:genetics / Q000276:immunology* / Q000472:pathogenicity*; D008253:Macaca mulatta; D018419:Primate Diseases / Q000276:immunology / Q000473:pathology / Q000821:virology; D013601:T-Lymphocytes / Q000276:immunology; D019562:Viral Load; D014764:Viral Proteins / Q000235:genetics* / Q000276:immunology*; D037521:Virulence Factors / Q000235:genetics / Q000276:immunology; D017735:Virus Latency
chemical_list: D016207:Cytokines; D014764:Viral Proteins; D037521:Virulence Factors; C073411:protein 61, Varicella-zoster virus