MOLECULAR PATHOGENESIS OF VARICELLA ZOSTER VIRUS INFECTION

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Simian varicella virus (SVV) infection of primates resembles human varicella-zoster virus (VZV) infection. After primary infection, SVV becomes latent in ganglia and reactivates after immunosuppression or social and environmental stress. Herein, natural SVV infection was established in 5 cynomolgus macaques (cynos) and 10 African green (AG) monkeys. Four cynos were treated with the immunosuppressant tacrolimus (80 to 300 ¿g/kg/day) for 4 months and 1 was untreated (group 1). Four AG monkeys were exposed to a single dose (200 cGy) of x-irradiation (group 2), and 4 other AG monkeys were irradiated and treated with tacrolimus for 4 months (group 3); the remaining 2 AG monkeys were untreated. Zoster rash developed 1 to 2 weeks after tacrolimus treatment in 3 of 4 monkeys in group 1, 6 weeks after irradiation in 1 of 4 monkeys in group 2, and 1 to 2 weeks after irradiation in all 4 monkeys in group 3. All monkeys were euthanized 1 to 4 months after immunosuppression. SVV antigens were detected immunohistochemically in skin biopsies as well as in lungs of most monkeys. Low copy number SVV DNA was detected in ganglia from all three groups of monkeys, including controls. RNA specific for SVV ORFs 61, 63, and 9 was detected in ganglia from one immunosuppressed monkey in group 1. SVV antigens were detected in multiple ganglia from all immunosuppressed monkeys in every group, but not in controls. These results indicate that tacrolimus treatment produced reactivation in more monkeys than irradiation and tacrolimus and irradiation increased the frequency of SVV reactivation as compared to either treatment alone. Studies of varicella-zoster virus gene expression during latency require the acquisition of human ganglia at autopsy. Concerns have been raised that the virus might reactivate immediately after death. Because features of varicella-zoster virus latency are similar in primate and human ganglia, we examined virus gene expression in tissues either processed immediately or kept at 4¿C for 30 h before necropsy of two monkeys inoculated with SVV and euthanized 117 days later. Virus transcription and the detection of open reading frame (ORF) 63 protein in the cytoplasm of neurons were comparable. Thus, a 30-h delay after death did not affect varicella-zoster virus expression in latently infected ganglia.