Analysis of T Cell Responses during Active Varicella-Zoster Virus Reactivation in Human Ganglia

Steain, Megan; Sutherland, Jeremy P; Rodriguez, Michael; Cunningham, Anthony L.; Slobedman, Barry; Abendroth, Allison

doi:10.1128/jvi.03445-13

Cited by 104 publications

(89 citation statements)

References 45 publications

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“…14,[26][27][28][29] In our study, the observation that vaccine efficacy was maintained even among patients in the oldest age group, in conjunction with previous clinical data showing that HZ/su immunogenicity decreases only minimally with increasing age, suggests that HZ/su can overcome immunosenescence to provide protection against herpes zoster. 19,21,30-32 The immune response to HZ/su in both older persons and those with immunosuppression that was observed in earlier clinical studies might be attributed to the AS01 B adjuvant system, which boosts VZV-specific memory immune responses.…”

Section: Discussionsupporting

confidence: 67%

Efficacy of an Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults

et al. 2015

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Section: Discussionsupporting

confidence: 67%

Efficacy of an Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults

et al. 2015

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“…This is in agreement with the immune mechanism that controls other herpesviral infections (27, 28) and with previous reports showing that adults with recent and/or frequent exposures to VZV, who did not develop symptomatic VZV infection, had robust VZV-specific CD8+ and CD4+ T cell responses detected by ex vivo restimulation (29–31). The important role of CD8+ T cells in the control of VZV replication could also be inferred from the accumulation of this T cell subset in the ganglia of individuals with HZ, where VZV is actively replicating (32). Furthermore, we showed that high frequencies of VZV-specific CD8+ CTL detected by ex vivo restimulation in HIV-infected children correlated with protection against HZ (33).…”

Section: Discussionmentioning

confidence: 99%

Varicella-Zoster Virus–Specific Cellular Immune Responses to the Live Attenuated Zoster Vaccine in Young and Older Adults

Weinberg

Canniff

Rouphael

et al. 2017

The Journal of Immunology

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The incidence and severity of herpes zoster (HZ) increases with age. The live attenuated zoster vaccine (ZV) generates immune responses similar to HZ. We compared the immune responses to ZV in young and older to adults to increase our understanding of the immune characteristics that may contribute to the increased susceptibility to HZ in older adults. Young (25–40 years; N=25) and older (60–80 years; N=33) adults had similar magnitude memory responses to varicella-zoster virus (VZV) ex-vivo restimulation measured by responder cell-frequency (RCF) and flow cytometry, but the responses were delayed in older compared with young adults. Only young adults had an increase in dual-function VZV-specific CD4+ and CD8+ T cell effectors defined by co-expression of IFNγ, IL2 and CD107a after vaccination. In contrast, older adults showed marginal increases in VZV-specific CD8+CD57+ senescent T cells after vaccination, which were already higher than those of young adults before vaccination. An increase in VZV-stimulated CD4+CD69+CD57+PD1+ and CD8+CD69+CD57+PD1+ T cells from baseline to post-vaccination was associated with concurrent decreased VZV-memory and CD8+ effector responses, respectively, in older adults. Blocking the PD1 pathway during ex-vivo VZV restimulation increased the CD4+ and CD8+ proliferation, but not the effector cytokine production, which modestly increased with TIM-3 blockade. We conclude that high proportions of senescent and exhausted VZV-specific T cells in the older adults contribute to their poor effector responses to a VZV challenge. This may underlie their inability to contain VZV reactivation and prevent the development of HZ.

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“…Previous studies report the presence of T cells (primarily noncytolytic CD8 ϩ T cells), B cells, macrophages, and natural killer cells within ganglia isolated from individuals who suffered from herpes zoster shortly before they died from other causes (7)(8)(9). These studies also showed increased expression of chemokine CXCL10, which binds to CXCR3 to induce migration of memory T cells and natural killer cells (8), as well as increased expression of major histocompatibility complex class I (MHC-I) and MHC-II molecules (9). These observations suggest that both innate and adaptive immunity play a critical role in the resolution of VZV reactivation.…”

mentioning

confidence: 99%

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

Arnold

Girke

Sureshchandra

et al. 2016

J Virol

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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...

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Analysis of T Cell Responses during Active Varicella-Zoster Virus Reactivation in Human Ganglia

Cited by 104 publications

References 45 publications

Efficacy of an Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults

Efficacy of an Adjuvanted Herpes Zoster Subunit Vaccine in Older Adults

Varicella-Zoster Virus–Specific Cellular Immune Responses to the Live Attenuated Zoster Vaccine in Young and Older Adults

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

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