T cells increase before zoster and PD-1 expression increases at the time of zoster in immunosuppressed nonhuman primates latently infected with simian varicella virus

James, Stephanie; Traina‐Dorge, Vicki; Deharo, Eileen; Wellish, Mary; Palmer, Brent E.; Gilden, Don; Mahalingam, Ravi

doi:10.1007/s13365-014-0237-7

Cited by 14 publications

(15 citation statements)

References 15 publications

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“…One of the markers of T cell dysfunction in this study, PD1, has been extensively studied in tumor and viral infections, including HZ, both in humans and in animal models (18, 19, 39, 40). Blocking the PD1 pathway in vivo significantly improves the cure rates in individuals with PDL1+ tumors.…”

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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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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“…Since T cell numbers increase at the time of zoster in immunosuppressed monkeys (19) and lymph nodes receive afferent neural input from the ganglia (20,21), analysis of ganglionic and lymph node tissues for virus DNA and antigens from monkeys within hours after SVV-specific T cell levels in blood are increased will help to determine whether reactivated SVV is transported transaxonally from the ganglia to the lymph nodes. Indeed, detection of SVV antigens in sweat glands (Fig.…”

Section: Discussionmentioning

confidence: 99%

Simian Varicella Virus Is Present in Macrophages, Dendritic Cells, and T Cells in Lymph Nodes of Rhesus Macaques after Experimental Reactivation

Traina‐Dorge

Doyle-Meyers

Sanford

et al. 2015

J Virol

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Like varicella-zoster virus (VZV), simian varicella virus (SVV) reactivates to produce zoster. In the present study, 5 rhesus macaques were inoculated intrabronchially with SVV, and 5 months later, 4 monkeys were immunosuppressed; 1 monkey was not immunosuppressed but was subjected to the stress of transportation. In 4 monkeys, a zoster rash developed 7 to 12 weeks after immunosuppression, and a rash also developed in the monkey that was not immunosuppressed. Analysis at 24 to 48 h after zoster revealed SVV antigen in the lung alveolar wall, in ganglionic neurons and nonneuronal cells, and in skin and in lymph nodes. In skin, SVV was found primarily in sweat glands. In lymph nodes, the SVV antigen colocalized mostly with macrophages, dendritic cells, and, to a lesser extent, T cells. The presence of SVV in lymph nodes, as verified by quantitative PCR detection of SVV DNA, might reflect the sequestration of virus by macrophages and dendritic cells in lymph nodes or the presentation of viral antigens to T cells to initiate an immune response against SVV, or both. IMPORTANCEVZV causes varicella (chickenpox), becomes latent in ganglia, and reactivates to produce zoster and multiple other serious neurological disorders. SVV in nonhuman primates has proved to be a useful model in which the pathogenesis of the virus parallels the pathogenesis of VZV in humans. Here, we show that SVV antigens are present in sweat glands in skin and in macrophages and dendritic cells in lymph nodes after SVV reactivation in monkeys, raising the possibility that macrophages and dendritic cells in lymph nodes serve as antigen-presenting cells to activate T cell responses against SVV after reactivation. P rimary varicella-zoster virus (VZV) infection produces chickenpox (varicella), after which the virus becomes latent in ganglionic neurons along the entire neuraxis. As VZV-specific T cell immunity declines with advancing age, VZV reactivates to produce zoster, which may be complicated by multiple neurological and ocular disorders. Simian varicella virus (SVV) infection of nonhuman primates has served as a good model with which to study the pathogenesis of VZV because of the pathological, immunological, and virological similarities of SVV to VZV (1, 2). VZV reactivation is increased in patients receiving chemotherapy or after X-irradiation (3); similarly, SVV reactivates in latently infected African green monkeys (AGM) and cynomolgus monkeys (CM) after immunosuppression and environmental stress (4). In rhesus macaques, intrabronchial inoculation with SVV produces varicella, followed by the establishment of latency (5) and virus reactivation after X-irradiation (6, 7). At the time of SVV reactivation in CM, expression of CXCL10 (a chemokine which recruits activated T cells and NK cells) correlates with transient T cell infiltration in ganglia (8). In the study described here, we determined if a combination of irradiation and treatment with prednisone and tacrolimus induces reactivation of SVV in latently infected rhesus macaques to s...

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“…Levels of both modulators returned to baseline at 6 to 7 weeks after immunosuppression (197 dpi) and before reactivation, suggesting their role in triggering viral reactivation. MCP-1 also recruits macro-phages into the nervous system and activates microglia (Selenica et al 2013; Deshmane et al 2009); thus, its expression could also indicate subclinical SVV reactivation (James et al 2014). Additional robust pro-inflammatory immune responses were revealed by induction of IL-6, IL-8, MIF, RANTES and HGF, while an anti-inflammatory response was represented by increased cytokine IL-1Ra levels after immunosuppression (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…Experimental inoculation of the five rhesus macaques with SVV and immunosuppressive treatment have been described earlier (James et al 2014). Briefly, five rhesus macaques (HB62, HI83 HF39, HC44 and HA95) were each inoculated intrabronchially with 10 4 plaque-forming units (pfu) of SVV ( n =3) or SVV-GFP (SVV expressing green fluorescent protein) ( n =2).…”

Section: Methodsmentioning

confidence: 99%

“…Simian varicella virus (SVV) infection of nonhuman primates is a useful animal model of VZV pathogenesis in humans (Mahalingam et al 2001, 2007, 2010a, b; Messaoudi et al 2009). Expression of CXCL10 correlates with T-cell infiltration in ganglia of macaques containing reactivated SVV (Ouwendijk et al 2013), and increases in circulating CD4+ and CD8+ T lymphocytes before and during SVV reactivation correlate with increases in cellular PD-1 expression (James et al 2014). Because the time of primary VZV infection and reactivation in humans cannot be predicted, in this work we identified and quantified expression of cytokines, chemokines, and growth factors in the peripheral circulation of SVV-infected rhesus macaques during acute varicella, latency and reactivation.…”

Section: Introductionmentioning

confidence: 99%

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Robust pro-inflammatory and lesser anti-inflammatory immune responses during primary simian varicella virus infection and reactivation in rhesus macaques

et al. 2014

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Simian varicella virus (SVV) infection of non-human primates models human varicella zoster virus (VZV) infection. Assessment of cell signaling immune responses in monkeys after primary SVV infection, after immunosuppression and during reactivation revealed strong pro-inflammatory responses and lesser anti-inflammatory components during varicella and reactivation. Pro-inflammatory mediators elevated during varicella included interferon-gamma (IFN-γ), interleukin (IL)-6, mono-cyte chemoattractant protein (MCP-1), interferon inducible T-cell α chemoattractant protein (I-TAC), interferon processing protein (IP-10), and anti-inflammatory interleukin-1 Receptor antagonist (IL-1Ra). After immunosuppression and at reactivation, levels of pro-inflammatory mediators MCP-1, eotaxin, IL-6, IL-8, MIF, RANTES (regulated-on-activation normal T-cell expressed and secreted), and HGF (hepatocyte growth factor) were elevated, as was the anti-inflammatory mediator IL-1Ra. Characterization of cytokine, chemokine and growth factor responses during different stages of varicella virus infection will facilitate immunotherapeutic and vaccine strategies.

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T cells increase before zoster and PD-1 expression increases at the time of zoster in immunosuppressed nonhuman primates latently infected with simian varicella virus

Cited by 14 publications

References 15 publications

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

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

Simian Varicella Virus Is Present in Macrophages, Dendritic Cells, and T Cells in Lymph Nodes of Rhesus Macaques after Experimental Reactivation

Robust pro-inflammatory and lesser anti-inflammatory immune responses during primary simian varicella virus infection and reactivation in rhesus macaques

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