Simian varicella virus infection of Chinese rhesus macaques produces ganglionic infection in the absence of rash

Varicella-zoster virus (VZV) causes varicella (chickenpox), becomes latent in ganglia along the entire neuraxis, and may reactivate to cause herpes zoster (shingles). VZV may infect ganglia via retrograde axonal transport from infected skin or through hematogenous spread. Simian varicella virus (SVV) infection of rhesus macaques provides a useful model system to study the pathogenesis of human VZV infection. To dissect the virus and host immune factors during acute SVV infection, we analyzed four SVV-seronegative Chinese rhesus macaques infected intratracheally with cell-associated 5 × 103 plaque-forming units (pfu) of SVV-expressing green fluorescent protein (n = 2) or 5 × 104 pfu of wild-type SVV (n = 2). All monkeys developed viremia and SVV-specific adaptive B- and T-cell immune responses, but none developed skin rash. At necropsy 21 days postinfection, SVV DNA was found in ganglia along the entire neuraxis and in viscera, and SVV RNA was found in ganglia, but not in viscera. The amount of SVV inoculum was associated with the extent of viremia and the immune response to virus. Our findings demonstrate that acute SVV infection of Chinese rhesus macaques leads to ganglionic infection by the hematogenous route and the induction of a virus-specific adaptive memory response in the absence of skin rash

Varicella zoster virus infection of highly pure terminally differentiated human neurons

In vitro analyses of varicella zoster virus (VZV) reactivation from latency in human ganglia have been hampered by the inability to isolate virus by explantation or cocultivation techniques. Furthermore, attempts to study interaction of VZV with neurons in experimentally infected ganglion cells in vitro have been impaired by the presence of nonneuronal cells, which become productively infected and destroy the cultures. We have developed an in vitro model of VZV infection in which highly pure (>95 %) terminally differentiated human neurons derived from pluripotent stem cells were infected with VZV. At 2 weeks post-infection, infected neurons appeared healthy compared to VZV-infected human fetal lung fibroblasts (HFLs), which developed a cytopathic effect (CPE) within 1 week. Tissue culture medium from VZV-infected neurons did not produce a CPE in uninfected HFLs and did not contain PCR-amplifiable VZV DNA, but cocultivation of infected neurons with uninfected HFLs did produce a CPE. The nonproductively infected neurons contained multiple regions of the VZV genome, as well as transcripts and proteins corresponding to VZV immediate-early, early, and late genes. No markers of the apoptotic caspase cascade were detected in healthy-appearing VZV-infected neurons. VZV infection of highly pure terminally differentiated human neurons provides a unique in vitro system to study the VZV-neuronal relationship and the potential to investigate mechanisms of VZV reactivation

T-Cell Tropism of Simian Varicella Virus during Primary Infection

Varicella-zoster virus (VZV) causes varicella, establishes a life-long latent infection of ganglia and reactivates to cause herpes zoster. The cell types that transport VZV from the respiratory tract to skin and ganglia during primary infection are unknown. Clinical, pathological, virological and immunological features of simian varicella virus (SVV) infection of non-human primates parallel those of primary VZV infection in humans. To identify the host cell types involved in virus dissemination and pathology, we infected African green monkeys intratracheally with recombinant SVV expressing enhanced green fluorescent protein (SVV-EGFP) and with wild-type SVV (SVV-wt) as a control. The SVV-infected cell types and virus kinetics were determined by flow cytometry and immunohistochemistry, and virus culture and SVV-specific real-time PCR, respectively. All monkeys developed fever and skin rash. Except for pneumonitis, pathology produced by SVV-EGFP was less compared to SVV-wt. In lungs, SVV infected alveolar myeloid cells and T-cells. During viremia the virus preferentially infected memory T-cells, initially central memory T-cells and subsequently effector memory T-cells. In early non-vesicular stages of varicella, SVV was seen mainly in perivascular skin infiltrates composed of macrophages, dendritic cells, dendrocytes and memory T-cells, implicating hematogenous spread. In ganglia, S

Varicella Zoster Virus DNA at Inoculation Sites and in Saliva After Zostavax Immunization

Analysis of 36 individuals over age 60 years who were immunized with Zostavax revealed varicella zoster virus (VZV) DNA in swabs of skin inoculation sites obtained immediately after immunization in 18 (50%) of 36 subjects (copy number per nanogram of total DNA, 28 to 2.1 × 106) and in saliva collected over 28 days in 21 (58%) of 36 subjects (copy number, 20 to 248). Genotypic analysis of DNA extracted from 9 random saliva samples identified vaccine virus in all instances. In some immunized individuals over age 60, vaccine virus DNA is shed in saliva up to 4 weeks