Dynamic Interplay between Varicelloviruses and their Primate Hosts

Abstract

Varicella-zoster virus (VZV) is a ubiquitous human alphaherpesvirus (αHHV). Most individuals become infected with VZV during childhood typically resulting in generalized vesicular skin rash, although a minority of individuals will not develop evident skin rash. During primary infection the virus gains access to ganglia along the entire neuraxis, where it establishes a life-long latent infection of mostly sensory neurons. Due to the long incubation period and restricted host range of the virus, the cell types involved in the dissemination of VZV from the site of primary infection to the virus’ target organs are largely unknown. Clinical, pathological, virological and immunological features of simian varicella virus (SVV) infection of nonhuman primates parallel those of primary VZV infection in humans. Consequently, the virus-host interactions involved in primary infection were studied in the SVV nonhuman primate model in Chapters 2 and 3 of this thesis. The latent phase of VZV is completely refractory to antiviral treatment and provides the virus the opportunity to reactivate later in life and cause herpes zoster. The mechanisms by which VZV latency is established and maintained remain enigmatic. Although cumulative data suggest that VZV latency is associated with restricted gene expression and possibly protein expression, considerable discrepancies have been reported in literature. The expression of VZV proteins and genes was reinvestigated in Chapters 4 and 5 of this thesis, providing novel insights into VZV latency. VZV reactivation as a result of declined virus-specific T-cell immunity causes herpes zoster or may occur asymptomatically. Asymptomatic shedding of the closely related αHHV HSV-1 occurs frequently, but the incidence of VZV shedding and its relation to HSV-1 shedding in that same individual is largely unknown. This was addressed in Chapter 6 of this thesis. Herpes zoster results from intraganglionic VZV replication followed by transaxonal spread of virus to the skin. Consequently, immune cells, mainly T-cells, infiltrate ganglia following herpes zoster most likely to control local virus replication. The stimulus driving T-cell infiltration and subsequent retention after VZV reactivation is ill-defined. The aim of the study described in Chapter 7 was to investigate this issue in ganglia of cynomolgus macaques obtained at variable intervals following SVV reactivation. Although virusspecific T-cells are essential for uncomplicated recovery from varicella and herpes zoster, VZV-specific T-cells may cause immunopathology in patients with VZV-induced uveitis. Chapter 8 describes the identification and functional characterization of ocular-derived VZV/HSV-1 cross-reactive CD4+ T-cells.