T-Cell Tropism of Simian Varicella Virus during Primary Infection

Ouwendijk, Werner J. D.; Mahalingam, Ravi; Swart, Rik L. de; Haagmans, Bart L.; Amerongen, Geert van; Getu, Sarah; Gilden, Don; Osterhaus, Albert D. M. E.; Verjans, Georges M. G. M.

doi:10.1371/journal.ppat.1003368

Cited by 44 publications

(100 citation statements)

References 54 publications

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“…SVV infection in nonhuman primates provides a model system with which to identify cells involved in the dissemination of varicella to multiple organs during primary infection as well as after reactivation. During experimental primary SVV infection in AGM, alveolar macrophages and dendritic cells become infected at 5 dpi and transfer virus to T cells in lymph nodes (12). In the study described here, we extended studies of SVV reactivation in rhesus macaques and demonstrated the presence of SVV in the sweat glands of skin and in the macrophages and dendritic cells of lymph nodes.…”

Section: Discussionsupporting

confidence: 57%

“…SVV-seronegative rhesus macaques (monkeys HB62, HI83, HF39, HC44, HA95, II49, and IK10) were inoculated intrabronchially with 10 4 PFU of wild-type SVV (monkeys HB62, HI83, HA95, II49, and IK10) or SVV expressing enhanced green fluorescent protein (SVV-EGFP) (monkeys HF39 and HC44) as described previously (4,10). Earlier, we demonstrated that SVV-EGFP is pathogenic in African green monkeys and that SVV-EGFP is mildly attenuated compared to wild-type SVV (11,12). All monkeys were monitored by physical exams every 2 or 3 days, and blood samples were collected either weekly or biweekly.…”

Section: Methodsmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 57%

Section: Methodsmentioning

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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“…Primary SVV infection results in viraemia ; however, SVV DNA is present in monkey ganglia prior to rash Ouwendijk et al, 2012c), indicating virus can infect ganglia during the viraemic stage of infection. This finding was recently confirmed and extended by the demonstration that SVV infects memory T-cells prior to rash and virus DNA is present in neurons, in close proximity to memory T-cells (Ouwendijk et al, 2013). In addition, VZV-infected T-cells, most likely memory T-cells (Ku et al, 2004), can transfer virus to engrafted human dorsal root ganglia in a model of VZV pathogenesis using severe combined immunodeficient (SCID) mice (Zerboni et al, 2005).…”

Section: Introductionmentioning

confidence: 61%

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

Kennedy

Rovnak

Badani

et al. 2015

Journal of General Virology

133

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Herpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses that cause lifelong infections in ganglia. Following primary infection and establishment of latency, HSV-1 reactivation typically results in herpes labialis (cold sores), but can occur frequently elsewhere on the body at the site of primary infection (e.g. whitlow), particularly at the genitals. Rarely, HSV-1 reactivation can cause encephalitis; however, a third of the cases of HSV-1 encephalitis are associated with HSV-1 primary infection. Primary VZV infection causes varicella (chickenpox) following which latent virus may reactivate decades later to produce herpes zoster (shingles), as well as an increasingly recognized number of subacute, acute and chronic neurological conditions. Following primary infection, both viruses establish a latent infection in neuronal cells in human peripheral ganglia. However, the detailed mechanisms of viral latency and reactivation have yet to be unravelled. In both cases latent viral DNA exists in an 'end-less' state where the ends of the virus genome are joined to form structures consistent with unit length episomes and concatemers, from which viral gene transcription is restricted. In latently infected ganglia, the most abundantly detected HSV-1 RNAs are the spliced products originating from the primary latency associated transcript (LAT). This primary LAT is an 8.3 kb unstable transcript from which two stable (1.5 and 2.0 kb) introns are spliced. Transcripts mapping to 12 VZV genes have been detected in human ganglia removed at autopsy; however, it is difficult to ascribe these as transcripts present during latent infection as early-stage virus reactivation may have transpired in the post-mortem time period in the ganglia. Nonetheless, low-level transcription of VZV ORF63 has been repeatedly detected in multiple ganglia removed as close to death as possible. There is increasing evidence that HSV-1 and VZV latency is epigenetically regulated. In vitro models that permit pathway analysis and identification of both epigenetic modulations and global transcriptional mechanisms of HSV-1 and VZV latency hold much promise for our future understanding in this complex area. This review summarizes the molecular biology of HSV-1 and VZV latency and reactivation, and also presents future directions for study. Received 5 January 2015Accepted 18 March 2015 IntroductionHerpes simplex virus type 1 (HSV-1; human herpesvirus 1) and varicella-zoster virus (VZV; human herpesvirus 3) are human neurotropic alphaherpesviruses usually acquired early in life. Primary HSV-1 infection is usually localized and may be asymptomatic, although it can produce a more widespread systemic infection in neonates and immunocompromised adults, whilst primary VZV infection is systemic and results in childhood varicella (chickenpox). During primary infection, both viruses gain access to neurons most likely through retrograde transport from the site of cutaneous lesion...

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“…Moreover, as described for VZV, SVV can reactivate during episodes of immune suppression and stress (11)(12)(13), and this reactivation is accompanied by the upregulation of CXCL10 and T cell infiltration (14). Recent studies using African green monkeys (AGMs) inoculated with SVV-enhanced green fluorescent protein (EGFP) have shown that SVV infects T cells that infiltrate the ganglia during acute infection 9 dpi (15). However, SVV infection of AGMs, in contrast to human VZV infection, results in significant mortality (16), and SVV-GFEP is attenuated compared to the wild type (WT) (15).…”

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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T-Cell Tropism of Simian Varicella Virus during Primary Infection

Cited by 44 publications

References 54 publications

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

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

A comparison of herpes simplex virus type 1 and varicella-zoster virus latency and reactivation

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

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