title: Simian varicella virus infection of rhesus macaques recapitulates essential features of varicella zoster virus infection in humans.
abstract: Simian varicella virus (SVV), the etiologic agent of naturally occurring varicella in primates, is genetically and antigenically closely related to human varicella zoster virus (VZV). Early attempts to develop a model of VZV pathogenesis and latency in nonhuman primates (NHP) resulted in persistent infection. More recent models successfully produced latency; however, only a minority of monkeys became viremic and seroconverted. Thus, previous NHP models were not ideally suited to analyze the immune response to SVV during acute infection and the transition to latency. Here, we show for the first time that intrabronchial inoculation of rhesus macaques with SVV closely mimics naturally occurring varicella (chickenpox) in humans. Infected monkeys developed varicella and viremia that resolved 21 days after infection. Months later, viral DNA was detected only in ganglia and not in non-ganglionic tissues. Like VZV latency in human ganglia, transcripts corresponding to SVV ORFs 21, 62, 63 and 66, but not ORF 40, were detected by RT-PCR. In addition, as described for VZV, SVV ORF 63 protein was detected in the cytoplasm of neurons in latently infected monkey ganglia by immunohistochemistry. We also present the first in depth analysis of the immune response to SVV. Infected animals produced a strong humoral and cell-mediated immune response to SVV, as assessed by immunohistology, serology and flow cytometry. Intrabronchial inoculation of rhesus macaques with SVV provides a novel model to analyze viral and immunological mechanisms of VZV latency and reactivation.
authors.affiliation: Vaccine and Gene Therapy, Division of Pathobiology and Immunology, Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon, United States of America. messaoud@ohsu.edu
authors.forename: Ilhem
authors.initials: I
authors.lastname: Messaoudi
authors.forename: Alexander
authors.initials: A
authors.lastname: Barron
authors.forename: Mary
authors.initials: M
authors.lastname: Wellish
authors.forename: Flora
authors.initials: F
authors.lastname: Engelmann
authors.forename: Alfred
authors.initials: A
authors.lastname: Legasse
authors.forename: Shannon
authors.initials: S
authors.lastname: Planer
authors.forename: Don
authors.initials: D
authors.lastname: Gilden
authors.forename: Janko
authors.initials: J
authors.lastname: Nikolich-Zugich
authors.forename: Ravi
authors.initials: R
authors.lastname: Mahalingam
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology; D049109:Cell Proliferation; D004279:DNA, Viral / Q000032:analysis; D004195:Disease Models, Animal; D006566:Herpesviridae Infections / Q000378:metabolism / Q000473:pathology; D014645:Herpesvirus 3, Human; D006801:Humans; D007150:Immunohistochemistry; D008253:Macaca mulatta / Q000821:virology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology; D018140:Varicellovirus / Q000235:genetics / Q000472:pathogenicity*; D019562:Viral Load
chemical_list: D004279:DNA, Viral