Abstract
Varicella zoster virus (VZV) is a neurotropic alphaherpesvirus and the causative agent of varicella (chickenpox) in humans. Following primary infection, VZV establishes latency in the sensory ganglia and can reactivate to cause herpes zoster, more commonly known as shingles, which causes significant morbidity, and on rare occasions mortality, in the elderly. Because VZV infection is highly restricted to humans, the development of a reliable animal model has been challenging, and our understanding of VZV pathogenesis remains incomplete. As an alternative, infection of rhesus macaques with the homologous simian varicella virus (SVV) recapitulates the hallmarks of VZV infection and thus constitutes a robust animal model to provide critical insights into VZV pathogenesis and the host antiviral response. In this model, SVV infection results in the development of varicella during primary infection, generation of an adaptive immune response, establishment of latency in the sensory ganglia, and viral reactivation upon immune suppression. In this review, we discuss our current knowledge about host and viral factors involved in the establishment of SVV latency and reactivation as well as the important role played by T cells in SVV pathogenesis and antiviral immunity.
Highlights
AND KNOWLEDGE GAPSVaricella zoster virus (VZV) is one of the nine human herpesviruses
The engraftment of different human fetal tissues in this model allowed direct inoculation of VZV and resulted in several important insights into VZV pathogenesis (Moffat et al, 1995; Ku et al, 2004; Zerboni et al, 2005; Reichelt et al, 2008; Wang et al, 2017). This model presents several limitations including: (1) direct inoculation into the human xenografts tissues does not mimic natural route of transmission; (2) the lack of adaptive immunity, which is critical to control viral infection; and (3) the possibility that the strict human host specificity of VZV may alter virus behavior in this model; (4) the use of the attenuated Oka vaccine strain in some of these studies, which compared to the parent wild type strain contains numerous nucleotide substitutions found in multiple open reading frames (ORFs) and may not accurately model the behavior of wild type virus strains (Jones and Arvin, 2003; Yamanishi, 2008; Sen et al, 2015). To overcome these limitations an alternative animal model was developed where non-human primates are inoculated with Simian varicella virus (SVV), an alphaherpesvirus that causes a vesicular rash in Old World monkeys
In both rhesus macaques and African green monkeys, different subsets of immune cells, including T cells, were shown to reach the ganglia as early as 3 days post intrabronchial inoculation during acute infection (Ouwendijk et al, 2013b; Arnold et al, 2016a), prior to the detection of antiSVV specific T cell immunity, these results suggest that T cells play an important role in simian varicella virus (SVV) dissemination to sensory ganglia
Summary
VZV establishes latency in the sensory ganglia and can reactivate to cause herpes zoster, more commonly known as shingles, which causes significant morbidity, and on rare occasions mortality, in the elderly. Infection of rhesus macaques with the homologous simian varicella virus (SVV) recapitulates the hallmarks of VZV infection and constitutes a robust animal model to provide critical insights into VZV pathogenesis and the host antiviral response. In this model, SVV infection results in the development of varicella during primary infection, generation of an adaptive immune response, establishment of latency in the sensory ganglia, and viral reactivation upon immune suppression.
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