Simian Varicella Virus Infection of Rhesus Macaques Recapitulates Essential Features of Varicella Zoster Virus Infection in Humans

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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. Varicella zoster virus (VZV) is a ubiquitous herpesvirus that causes chickenpox (varicella) and establishes a life-long latent infection in humans. VZV can then reactivate causing herpes zoster, commonly known as shingles, a painful and debilitating disease that can be life-threatening in elderly and immunocompromised individuals. Our understanding of immunological factors that control VZV replication is limited due to the fact that VZV causes disease only in humans. Simian varicella virus (SVV) is a simian counterpart of VZV that infects nonhuman primates. Our study showed for the first time that infection of rhesus macaques with SVV recapitulates key aspects of VZV infection from chickenpox and the resolution of acute viremia to the establishment of latency in ganglia, and the development of B and T cell responses to virus. This model will allow us to improve our understanding of the immune response to varicella virus, and to develop and test vaccines and antiviral drugs that can reduce the incidence of shingles and its attendant neurological complications.

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