Varicella-zoster virus (VZV), an exclusively human herpesvirus, causes chickenpox and establishes a latent infection in ganglia, reactivating decades later to produce zoster and associated neurological complications. An understanding of VZV neurotropism in humans has long been hampered by the lack of an adequate animal model. For example, experimental inoculation of VZV in small animals including guinea pigs and cotton rats results in the infection of ganglia but not a rash. The severe combined immune deficient human (SCID-hu) model allows the study of VZV neurotropism for human neural sub-populations. Simian varicella virus (SVV) infection of rhesus macaques (RM) closely resembles both human primary VZV infection and reactivation, with analyses at early times after infection providing valuable information about the extent of viral replication and the host immune responses. Indeed, a critical role for CD4 T-cell immunity during acute SVV infection as well as reactivation has emerged based on studies using RM. Herein we discuss the results of efforts from different groups to establish an animal model of VZV neurotropism.

HIV vaccine mediated efficacy, using an expanded live attenuated recombinant varicella virus-vectored SIV rSVV-SIVgag/env vaccine prime with adjuvanted SIV-Env and SIV-Gag protein boosts, was evaluated in a female rhesus macaques (RM) model against repeated intravaginal SIV challenges. Vaccination induced anti-SIV IgG responses and neutralizing antibodies were found in all vaccinated RMs. Three of the eight vaccinated RM remained uninfected (vaccinated and protected, VP) after 13 repeated challenges with the pathogenic SIVmac251-CX-1. The remaining five vaccinated and infected (VI) macaques had significantly reduced plasma viral loads compared with the infected controls (IC). A significant increase in systemic central memory CD4+ T cells and mucosal CD8+ effector memory T-cell responses was detected in vaccinated RMs compared to controls. Variability in lymph node SIV-Gag and Env specific CD4+ and CD8+ T cell cytokine responses were detected in the VI RMs while all three VP RMs had more durable cytokine responses following vaccination and prior to challenge. VI RMs demonstrated predominately SIV-specific monofunctional cytokine responses while the VP RMs generated polyfunctional cytokine responses. This study demonstrates that varicella virus-vectored SIV vaccination with protein boosts induces a 37.5% efficacy rate against pathogenic SIV challenge by generating mucosal memory, virus specific neutralizing antibodies, binding antibodies, and polyfunctional T-cell responses.

Varicella zoster virus (VZV) and simian varicella virus (SVV) cause varicella (chickenpox) in children and nonhuman primates, respectively. After resolution of acute disease, the viruses establish latent infection in neural ganglia, after which they may reactivate to cause a secondary disease, such as herpes zoster. SVV infection of nonhuman primates provides a model to investigate VZV pathogenesis and antiviral strategies. The VZV and SVV genomes are similar in size and structure and share 70–75% DNA homology. SVV and VZV DNAs are co-linear in gene arrangement with the exception of the left end of the viral genomes. Viral gene expression is regulated into immediate early, early, and late transcription during in vitro and in vivo infection. During viral latency, VZV and SVV gene expression is limited to transcription of a viral latency-associated transcript (VLT). VZV and SVV are closely related alphaherpesviruses that likely arose from an ancestral varicella virus that evolved through cospeciation into species-specific viruses.