Genome-Wide Analysis of T Cell Responses during Acute and Latent Simian Varicella Virus Infections in Rhesus Macaques

Girke

Sureshchandra

et al. 2016

J Virol

Self Cite

Primary infection with varicella-zoster virus (VZV), a neurotropic alphaherpesvirus, results in varicella. VZV establishes latency in the sensory ganglia and can reactivate later in life to cause herpes zoster. The relationship between VZV and its host during acute infection in the sensory ganglia is not well understood due to limited access to clinical specimens. Intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV) recapitulates the hallmarks of VZV infection in humans. We leveraged this animal model to characterize the host-pathogen interactions in the ganglia during both acute and latent infection by measuring both viral and host transcriptomes on days postinfection (dpi) 3, 7, 10, 14, and 100. SVV DNA and transcripts were detected in sensory ganglia 3 dpi, before the appearance of rash. CD4 and CD8 T cells were also detected in the sensory ganglia 3 dpi. Moreover, lung-resident T cells isolated from the same animals 3 dpi also harbored SVV DNA and transcripts, suggesting that T cells may be responsible for trafficking SVV to the ganglia. Transcriptome sequencing (RNA-Seq) analysis showed that cessation of viral transcription 7 dpi coincides with a robust antiviral innate immune response in the ganglia. Interestingly, a significant number of genes that play a critical role in nervous system development and function remained downregulated into latency. These studies provide novel insights into host-pathogen interactions in the sensory ganglia during acute varicella and demonstrate that SVV infection results in profound and sustained changes in neuronal gene expression. IMPORTANCEMany aspects of VZV infection of sensory ganglia remain poorly understood, due to limited access to human specimens and the fact that VZV is strictly a human virus. Infection of rhesus macaques with simian varicella virus (SVV), a homolog of VZV, provides a robust model of the human disease. Using this model, we show that SVV reaches the ganglia early after infection, most likely by T cells, and that the induction of a robust innate immune response correlates with cessation of virus transcription. We also report significant changes in the expression of genes that play an important role in neuronal function. Importantly, these changes persist long after viral replication ceases. Given the homology between SVV and VZV, and the genetic and physiological similarities between rhesus macaques and humans, our results provide novel insight into the interactions between VZV and its human host and explain some of the neurological consequences of VZV infection. V aricella-zoster virus (VZV) is a neurotropic alphaherpesvirus and the causative agent of varicella (chickenpox) (1). VZV establishes latency in the sensory ganglia and can reactivate later in life to cause herpes zoster (shingles), a painful disease that affects almost 1 million individuals in the United States alone (2). VZV is transmitted through the inhalation of virus-laden saliva droplets or by direct contact with the infectious fluid from vesicles...

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Acute Simian Varicella Virus Infection Causes Robust and Sustained Changes in Gene Expression in the Sensory Ganglia

Girke

Sureshchandra

et al. 2016

J Virol

Self Cite

“…Intracellular cytokine staining (ICS). PBMC and BAL cells were stimulated ex vivo with SVV lysate (1 g) or with an overlapping peptide pool representing ORFs 4, 11, 16, 31, and 37 (1 g) for 1 h followed by the addition of brefeldin A (Sigma, St. Louis, MO) for an additional 14 h. We have recently shown that all 5 ORFs are highly immunogenic during acute SVV infection, and the cumulative response accounts for 20% of the total acute T cell response (29). After incubation, cells were stained with antibodies directed against CD4 and CD8␤.…”

Section: Methodsmentioning

confidence: 99%

Intrabronchial Infection of Rhesus Macaques with Simian Varicella Virus Results in a Robust Immune Response in the Lungs

Haberthur

Meyer

et al. 2014

J Virol

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Varicella-zoster virus (VZV) is the etiological agent of varicella (chickenpox) and herpes zoster (shingles). Primary VZV infection is believed to occur via the inhalation of virus either in respiratory droplets or from shedding varicella lesions or by direct contact with infectious vesicular fluid. However, the ensuing immune response in the lungs remains incompletely understood. We have shown that intrabronchial inoculation of rhesus macaques with simian varicella virus (SVV), a homolog of VZV, recapitulates the hallmarks of acute and latent VZV infection in humans. In this study, we performed an in-depth analysis of the host immune response to acute SVV infection in the lungs and peripheral blood. We report that acute SVV infection results in a robust innate immune response in the lungs, characterized by the production of inflammatory cytokines, chemokines, and growth factors as well as an increased frequency of plasmacytoid dendritic cells (DCs) that corresponded with alpha interferon (IFN-␣) production and a rapid decrease in viral loads in the lungs. This is followed by T and B cell proliferation, antibody production, T cell differentiation, and cytokine production, which correlate with the complete cessation of viral replication. Although terminally differentiated CD8 T cells became the predominant T cell population in bronchoalveolar lavage cells, a higher percentage of CD4 T cells were SVV specific, which suggests a critical role for these cells in the resolution of primary SVV infection in the lungs. Given the homology between SVV and VZV, our data provide insight into the immune response to VZV within the lung. IMPORTANCEAlthough primary VZV infection occurs primarily via the respiratory route, the host response in the lungs and its contribution to the cessation of viral replication and establishment of latency remain poorly understood. The difficulty in accessing lung tissue and washes from individuals infected with VZV has hampered efforts to address this knowledge gap. SVV infection of rhesus macaques is an important model of VZV infection of humans; therefore, we utilized this animal model to gain a comprehensive view of the kinetics of the immune response to SVV in the lung and its relationship to the resolution of acute infection in respiratory tissues. These data not only advance our understanding of host immunity to VZV, a critical step in developing new vaccines, but also provide additional insight into immunity to respiratory pathogens. P rimary infection with varicella-zoster virus (VZV), a neurotropic alphaherpesvirus, occurs primarily through the inhalation of virus-laden saliva droplets (1, 2) or airborne virions from varicella lesions (3) or by contact with infectious vesicular fluid (4). The incubation period of varicella can range from 10 to 21 days and usually results in a benign self-limiting disease characterized by the appearance of vesicular exanthem, fever, and malaise (5). Current evidence suggests VZV can infect and replicate within the respiratory mucosal epithelium....

“…During latent infection, T cell responses were reduced significantly in magnitude and breadth compared to those observed during acute infection . Interestingly, T cell responses against ORF4, ORF11, ORF19, ORF31 and ORF 37 were maintained into latency, albeit at lower levels, whereas T cell responses to ORF10, ORF20, ORF29, ORF31, ORF62, ORF63 and ORF68 showed a significant decrease of about 83% between primary and latent infection . These observations may explain the success of the subunit vaccine HZ/su, which contains adjuvanted ORF68 protein and can potentially aid in the development of a multivalent subunit vaccine.…”

Section: Animal Models Of Vzv Studiesmentioning

confidence: 89%

Herpes zoster and the search for an effective vaccine

Clinical and Experimental Immunology

Messaoudi

2016

SummaryPrimary infection with varicella zoster virus (VZV), an exclusively human neurotrophic alphaherpsesvirus, results in varicella, known more commonly as chickenpox. Like other alphaherpesviruses, VZV establishes latency in the sensory ganglia and can reactivate to cause herpes zoster (also known as shingles), a painful and debilitating disease, especially in elderly and immunocompromised individuals. The overall incidence of herpes zoster in Europe and the United States is three per 1000 people, but increases sharply after 60 years of age to 10 per 1000 people. Zostavax V R is a vaccine approved by the Federal Drug Administration for the prevention of herpes zoster. Unfortunately, this vaccine reduces the incidence of disease by only 51% and the incidence of post-herpetic neuralgia by 66Á5% when administered to those aged 60 and older. Moreover, it is contraindicated for individuals who are immunocompromised or receiving immunosuppressant treatments, although they are at higher risk for herpes zoster compared to immunecompetent older individuals. This paper reviews VZV pathogenesis, host responses and current vaccines available to prevent herpes zoster.