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Wayne L Gray - One of the best experts on this subject based on the ideXlab platform.

  • current in vivo models of Varicella zoster Virus neurotropism
    Viruses, 2019
    Co-Authors: Ravi Mahalingam, Leigh Zerboni, Wayne L Gray, Ilhem Messaoudi, Michael D. Gershon, Anne A. Gershon, Ann M. Arvin, Jeffrey I Cohen, Vicki Trainadorge
    Abstract:

    Varicella-zoster Virus (VZV), an exclusively human herpesVirus, causes chickenpox and establishes a latent infection in ganglia, reactivating decades later to produce zoster and associated neurological complications. An understanding of VZV neurotropism in humans has long been hampered by the lack of an adequate animal model. For example, experimental inoculation of VZV in small animals including guinea pigs and cotton rats results in the infection of ganglia but not a rash. The severe combined immune deficient human (SCID-hu) model allows the study of VZV neurotropism for human neural sub-populations. Simian Varicella Virus (SVV) infection of rhesus macaques (RM) closely resembles both human primary VZV infection and reactivation, with analyses at early times after infection providing valuable information about the extent of viral replication and the host immune responses. Indeed, a critical role for CD4 T-cell immunity during acute SVV infection as well as reactivation has emerged based on studies using RM. Herein we discuss the results of efforts from different groups to establish an animal model of VZV neurotropism.

  • Characterization and mapping of Simian Varicella Virus transcripts
    2015
    Co-Authors: Wayne L Gray, Nanette J. Gusick, Thomas M. Fletcher, Carla Y Pumphrey
    Abstract:

    The size and genomic location of viral transcripts expressed in Simian variceUa Virus (SVV)-infected Vero cells were determined. Total cellular RNA and poly-adenylated RNA were isolated from SVV-infected and mock-infected Vero cells. Viral transcripts were detected by Northern blot hybridization analysis using over-lapping SVV DNA probes representative of the entire SW genome. The results indicated that all regions of the SVV genome are transcribed during SVV infection in vitro. At least 53 distinct viral RNA species ranging in size from 9.2 to 0.8 kb were detected. DNA probes derived from the SVV DNA long (L) and short (S) components hybridized to 44 RNAs (9-2 to 0"8 kb) and nine RNAs (4"9 to 0.8 kb), respectively. A transcript map of the SVV genome was constructed. The comparison made between the transcript maps of SVV and Varicella-zoster Virus (VZV) provides further support that the SVV and VZV genomes have an analogous gene organization. Simian Varicella is a natural, exanthematous di ease of non-human primates. Epizootics of Simian Varicella have occurred world-wide in captive populations of African green monkeys (Cercopithecus aethiops), patas monkeys (Erythrocebus patas) and several species of macaque monkeys (Macaca sp.) (Oakes & d'Offay, 1988). The disease ischaracterized by fever and vesicular rash and is clinically and pathogenically similar to human Varicella-zoster Virus (VZV) infections (Padovan & Cantrell, 1986). Simian Varicella is used therefore as an animal model for the study of VZV pathogenesis and latency and for the evaluation of antiviral agents and vaccine

  • bacterial artificial chromosome derived Simian Varicella Virus is pathogenic in vivo
    Virology Journal, 2013
    Co-Authors: Christine Meyer, Wayne L Gray, Nicole Arnold, Jesse Dewane, Kristen Haberthur, Flora Engelmann, Ilhem Messaoudi
    Abstract:

    Varicella zoster Virus (VZV) is a neurotropic alphaherpesVirus that infects humans and results in chickenpox and herpes zoster. A number of VZV genes remain functionally uncharacterized and since VZV is an obligate human pathogen, rigorous evaluation of VZV mutants in vivo remains challenging. Simian Varicella Virus (SVV) is homologous to VZV and SVV infection of rhesus macaques (RM) closely mimics VZV infection of humans. Recently the SVV genome was cloned as a bacterial artificial chromosome (BAC) and BAC-derived SVV displayed similar replication kinetics as wild-type (WT) SVV in vitro. RMs were infected with BAC-derived SVV or WT SVV at 4x105 PFU intrabronchially (N=8, 4 per group, sex and age matched). We collected whole blood (PBMC) and bronchoalveolar lavage (BAL) at various days post-infection (dpi) and sensory ganglia during latent infection (>84 dpi) at necropsy and compared disease progression, viral replication, immune response and the establishment of latency. Viral replication kinetics and magnitude in bronchoalveolar lavage cells and whole blood as well as rash severity and duration were similar in RMs infected with SVV BAC or WT SVV. Moreover, SVV-specific B and T cell responses were comparable between BAC and WT-infected animals. Lastly, we measured viral DNA in sensory ganglia from both cohorts of infected RMs during latent infection. SVV BAC is as pathogenic and immunogenic as WT SVV in vivo. Thus, the SVV BAC genetic system combined with the rhesus macaque animal model can further our understanding of viral ORFs important for VZV pathogenesis and the development of second-generation vaccines.

  • attenuation of the adaptive immune response in rhesus macaques infected with Simian Varicella Virus lacking open reading frame 61
    Journal of Virology, 2013
    Co-Authors: Christine Meyer, Wayne L Gray, Ilhem Messaoudi, Amelia Kerns, Jesse Dewane, Kristen Haberthur, Joshua M Walker
    Abstract:

    Varicella zoster Virus (VZV) is a neurotropic alphaherpesVirus that causes chickenpox during primary infection and establishes latency in sensory ganglia. Infection of rhesus macaques (RM) with the homologous Simian Varicella Virus (SVV) recapitulates hallmarks of VZV infection. We have shown that an antisense transcript of SVV open reading frame 61 (ORF61), a viral transactivator, was detected most frequently in latently infected RM sensory ganglia. In this study, we compared disease progression, viral replication, immune response, and the establishment of latency following intrabronchial infection with a recombinant SVV lacking ORF61 (SVVΔORF61) to those following infection with wild-type (WT) SVV. Varicella severity and viral latency within sensory ganglia were comparable in RMs infected with SVVΔORF61 and WT SVV. In contrast, viral loads, B and T cell responses, and plasma inflammatory cytokine levels were decreased in RMs infected with SVVΔORF61. To investigate the mechanisms underlying the reduced adaptive immune response, we compared acute SVV gene expression, frequency and proliferation of dendritic cell (DC) subsets, and the expression of innate antiviral genes in bronchoalveolar lavage (BAL) samples. The abundance of SVV transcripts in all kinetic classes was significantly decreased in RMs infected with SVVΔORF61. In addition, we detected a higher frequency and proliferation of plasmacytoid dendritic cells in BAL fluid at 3 days postinfection in RMs infected with SVVΔORF61, which was accompanied by a slight increase in type I interferon gene expression. Taken together, our data suggest that ORF61 plays an important role in orchestrating viral gene expression in vivo and interferes with the host antiviral interferon response.

  • increased cellular immune responses and cd4 t cell proliferation correlate with reduced plasma viral load in siv challenged recombinant Simian Varicella Virus Simian immunodeficiency Virus rsvv siv vaccinated rhesus macaques
    Virology Journal, 2012
    Co-Authors: Bapi Pahar, Wayne L Gray, Eileen Deharo, Kimberly Phelps, Elizabeth S Didier, Preston A Marx, Vicki Trainadorge
    Abstract:

    An effective AIDS vaccine remains one of the highest priorities in HIV-research. Our recent study showed that vaccination of rhesus macaques with recombinant Simian Varicella Virus (rSVV) vector – Simian immunodeficiency Virus (SIV) envelope and gag genes, induced neutralizing antibodies and cellular immune responses to SIV and also significantly reduced plasma viral loads following intravenous pathogenic challenge with SIVMAC251/CX1. The purpose of this study was to define cellular immunological correlates of protection in rSVV-SIV vaccinated and SIV challenged animals. Immunofluorescent staining and multifunctional assessment of SIV-specific T-cell responses were evaluated in both Experimental and Control vaccinated animal groups. Significant increases in the proliferating CD4+ T-cell population and polyfunctional T-cell responses were observed in all Experimental-vaccinated animals compared with the Control-vaccinated animals. Increased CD4+ T-cell proliferation was significantly and inversely correlated with plasma viral load. Increased SIV-specific polyfunctional cytokine responses and increased proliferation of CD4+ T-cell may be crucial to control plasma viral loads in vaccinated and SIVMAC251/CX1 challenged macaques.

Donald H. Gilden - One of the best experts on this subject based on the ideXlab platform.

  • characterization of the immune response in ganglia after primary Simian Varicella Virus infection
    Journal of NeuroVirology, 2016
    Co-Authors: Werner J. D. Ouwendijk, Ravi Mahalingam, Georges M. G. M. Verjans, Donald H. Gilden, Albert D. M. E. Osterhaus, Sarah Getu
    Abstract:

    Primary Simian Varicella Virus (SVV) infection in non-human primates causes Varicella, after which the Virus becomes latent in ganglionic neurons and reactivates to cause zoster. The host response in ganglia during establishment of latency is ill-defined. Ganglia from five African green monkeys (AGMs) obtained at 9, 13, and 20 days post-intratracheal SVV inoculation (dpi) were analyzed by ex vivo flow cytometry, immunohistochemistry, and in situ hybridization. Ganglia at 13 and 20 dpi exhibited mild inflammation. Immune infiltrates consisted mostly of CD8dim and CD8bright memory T cells, some of which expressed granzyme B, and fewer CD11c+ and CD68+ cells. Chemoattractant CXCL10 transcripts were expressed in neurons and infiltrating inflammatory cells but did not co-localize with SVV open reading frame 63 (ORF63) RNA expression. Satellite glial cells expressed increased levels of activation markers CD68 and MHC class II at 13 and 20 dpi compared to those at 9 dpi. Overall, local immune responses emerged as viral DNA load in ganglia declined, suggesting that intra-ganglionic immunity contributes to restricting SVV replication.

  • Simian Varicella Virus is present in skin tissue of rhesus macaques after experimental reactivation
    New Horizons in Translational Medicine, 2015
    Co-Authors: A Miller, Donald H. Gilden, Mary Wellish, V Trainadorge, Anna M Blackmon, Eileen Deharo, Ravi Mahalingam
    Abstract:

    Varicella zoster Virus (VZV) causes Varicella (chickenpox), establishes latency in ganglia and reactivates decades later to produce zoster in the elderly. Clinical, pathological, immunological and virological features of Simian Varicella Virus (SVV) infection of primates parallel human VZV infection. Primary SVV infection of primates, cause Varicella, after which Virus becomes latent in ganglionic neurons and reactivates upon social and environmental stress. Five rhesus macaques were infected intrabronchially with 4.0x10 5 pfu of SVV. Two weeks later, the monkeys developed Varicella rash. Twenty months later four of the monkeys were treated once with a 50 mg/kg of anti-CD4 antibody. All 5 monkeys developed zoster rash, 7–55 days after the treatment. Punch biopsies of the skin rash were analyzed for the presence of SVV antigens by immunohistochemistry and immunofluorescence. SVV ORF 63 protein and glycoproteins gH and L were detected in sweat glands in skin from all 5 monkeys. Presence of SVV in the β-3-tubilin-positive nerve endings in affected skin suggested possible route of skin infection during zoster.

  • robust pro inflammatory and lesser anti inflammatory immune responses during primary Simian Varicella Virus infection and reactivation in rhesus macaques
    Journal of NeuroVirology, 2014
    Co-Authors: Vicki Trainadorge, Donald H. Gilden, Mary Wellish, Stephanie James, Robert Sanford, Lara A Doylemeyers, Eileen De Haro, Ravi Mahalingam
    Abstract:

    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, monocyte 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.

  • 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
    Journal of NeuroVirology, 2014
    Co-Authors: Stephanie James, Vicki Trainadorge, Donald H. Gilden, Mary Wellish, Eileen Deharo, Brent E Palmer, Ravi Mahalingam
    Abstract:

    Like Varicella zoster Virus in humans, Simian Varicella Virus (SVV) becomes latent in ganglionic neurons along the entire neuraxis and reactivates in immunosuppressed monkeys. Five rhesus macaques were inoculated with SVV; 142 days later (latency), four monkeys were immunosuppressed, and T cells were analyzed for naive, memory, and effector phenotypes and expression of programmed death receptor-1 (PD-1; T cell exhaustion). All T cell subsets decreased during immunosuppression and except for CD8 effectors, peaked 2 weeks before zoster. Compared to before immunosuppression, PD-1 expression increased at reactivation. Increased T cells before zoster is likely due to Virus reactivation.

  • t cell tropism of Simian Varicella Virus during primary infection
    PLOS Pathogens, 2013
    Co-Authors: Werner J. D. Ouwendijk, Ravi Mahalingam, Donald H. Gilden, Albert D. M. E. Osterhaus, Sarah Getu, Rik L. De Swart, Bart L. Haagmans, Geert Van Amerongen, Georges M. G. M. Verjans
    Abstract:

    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, SVV was found primarily in neurons and occasionally in memory T-cells adjacent to neurons. In conclusion, the data suggest the role of memory T-cells in disseminating SVV to its target organs during primary infection of its natural and immunocompetent host.

Ravi Mahalingam - One of the best experts on this subject based on the ideXlab platform.

  • histopathological analysis of adrenal glands after Simian Varicella Virus infection
    Viruses, 2021
    Co-Authors: Christy S Niemeyer, Ravi Mahalingam, Teresa Mescher, Rocio Griggs, David J Orlicky, Gregory K Wilkerson, Andrew N Bubak, James E Hassell, Brittany Feia, Vicki Trainadorge
    Abstract:

    Latent Varicella zoster Virus (VZV) has been detected in human adrenal glands, raising the possibility of Virus-induced adrenal damage and dysfunction during primary infection or reactivation. Rare cases of bilateral adrenal hemorrhage and insufficiency associated with VZV reactivation have been reported. Since there is no animal model for VZV infection of adrenal glands, we obtained adrenal glands from two non-human primates (NHPs) that spontaneously developed Varicella from primary Simian Varicella Virus (SVV) infection, the NHP VZV homolog. Histological and immunohistochemical analysis revealed SVV antigen and DNA in the adrenal medulla and cortex of both animals. Adrenal glands were observed to have Cowdry A inclusion bodies, cellular necrosis, multiple areas of hemorrhage, and varying amounts of polymorphonuclear cells. No specific association of SVV antigen with βIII-tubulin-positive nerve fibers was found. Overall, we found that SVV can productively infect NHP adrenal glands, and is associated with inflammation, hemorrhage, and cell death. These findings suggest that further studies are warranted to examine the contribution of VZV infection to human adrenal disease. This study also suggests that VZV infection may present itself as acute adrenal dysfunction with “long-hauler” symptoms of fatigue, weakness, myalgias/arthralgias, and hypotension.

  • Elevated serum substance P during Simian Varicella Virus infection in rhesus macaques: implications for chronic inflammation and adverse cerebrovascular events
    Journal of NeuroVirology, 2020
    Co-Authors: Andrew N Bubak, Ravi Mahalingam, Vicki Traina-dorge, Brittany Feia, Christina N. Como, Catherine M. Pearce, Laura Doyle-meyers, Arpita Das, Jayme Looper, Maria A. Nagel
    Abstract:

    Varicella and zoster, produced by Varicella-zoster Virus (VZV), are associated with an increased risk of stroke that may be due to persistent inflammation and hypercoagulability. Because substance P is associated with inflammation, hypercoagulability, and atherosclerotic plaque rupture that may contribute to increased stroke risk after VZV infection, we measured serum substance P in Simian Varicella Virus–infected rhesus macaques. We found significantly increased and persistent serum substance P concentrations during Varicella and zoster compared with pre-inoculation, supporting the hypothesis that VZV-induced increases in serum substance P may contribute to increased stroke risk associated with VZV infection.

  • current in vivo models of Varicella zoster Virus neurotropism
    Viruses, 2019
    Co-Authors: Ravi Mahalingam, Leigh Zerboni, Wayne L Gray, Ilhem Messaoudi, Michael D. Gershon, Anne A. Gershon, Ann M. Arvin, Jeffrey I Cohen, Vicki Trainadorge
    Abstract:

    Varicella-zoster Virus (VZV), an exclusively human herpesVirus, causes chickenpox and establishes a latent infection in ganglia, reactivating decades later to produce zoster and associated neurological complications. An understanding of VZV neurotropism in humans has long been hampered by the lack of an adequate animal model. For example, experimental inoculation of VZV in small animals including guinea pigs and cotton rats results in the infection of ganglia but not a rash. The severe combined immune deficient human (SCID-hu) model allows the study of VZV neurotropism for human neural sub-populations. Simian Varicella Virus (SVV) infection of rhesus macaques (RM) closely resembles both human primary VZV infection and reactivation, with analyses at early times after infection providing valuable information about the extent of viral replication and the host immune responses. Indeed, a critical role for CD4 T-cell immunity during acute SVV infection as well as reactivation has emerged based on studies using RM. Herein we discuss the results of efforts from different groups to establish an animal model of VZV neurotropism.

  • reactivation of Simian Varicella Virus in rhesus macaques after cd4 t cell depletion
    Journal of Virology, 2019
    Co-Authors: Vicki Trainadorge, Brent E Palmer, Lara A Doylemeyers, Colin Coleman, Meredith Hunter, Amy Frieman, Anah Gilmore, Karen Altrock, M Nagel, Ravi Mahalingam
    Abstract:

    Rhesus macaques intrabronchially inoculated with Simian Varicella Virus (SVV), the counterpart of human Varicella-zoster Virus (VZV), developed primary infection with viremia and rash, which resolved upon clearance of viremia, followed by the establishment of latency. To assess the role of CD4 T cell immunity in reactivation, monkeys were treated with a single 50-mg/kg dose of a humanized monoclonal anti-CD4 antibody; within 1 week, circulating CD4 T cells were reduced from 40 to 60% to 5 to 30% of the total T cell population and remained low for 2 months. Very low viremia was seen only in some of the treated monkeys. Zoster rash developed after 7 days in the monkey with the most extensive CD4 T cell depletion (5%) and in all other monkeys at 10 to 49 days posttreatment, with recurrent zoster in one treated monkey. SVV DNA was detected in the lung from two of five monkeys, in bronchial lymph nodes from one of the five monkeys, and in ganglia from at least two dermatomes in three of five monkeys. Immunofluorescence analysis of skin rash, lungs, lymph nodes, and ganglia revealed SVV ORF63 protein at the following sites: sweat glands in skin; type II cells in lung alveoli, macrophages, and dendritic cells in lymph nodes; and the neuronal cytoplasm of ganglia. Detection of SVV antigen in multiple tissues upon CD4 T cell depletion and Virus reactivation suggests a critical role for CD4 T cell immunity in controlling Varicella Virus latency.IMPORTANCE Reactivation of latent VZV in humans can result in serious neurological complications. VZV-specific cell-mediated immunity is critical for the maintenance of latency. Similar to VZV in humans, SVV causes Varicella in monkeys, establishes latency in ganglia, and reactivates to produce shingles. Here, we show that depletion of CD4 T cells in rhesus macaques results in SVV reactivation, with Virus antigens found in zoster rash and SVV DNA and antigens found in lungs, lymph nodes, and ganglia. These results suggest the critical role of CD4 T cell immunity in controlling Varicella Virus latency.

  • Simian Varicella Virus Infects Enteric Neurons and α4β7 Integrin-Expressing Gut-Tropic T-Cells in Nonhuman Primates.
    Viruses, 2018
    Co-Authors: Werner J. D. Ouwendijk, Ravi Mahalingam, Suzanne C. Van Veen, Tamana Mehraban, Georges M. G. M. Verjans
    Abstract:

    The pathogenesis of enteric zoster, a rare debilitating complication of reactivation of latent Varicella-zoster Virus (VZV) in the enteric nervous system (ENS), is largely unknown. Infection of monkeys with the closely related VaricelloVirus Simian Varicella Virus (SVV) mimics VZV disease in humans. In this study, we determined the applicability of the SVV nonhuman primate model to study VaricelloVirus infection of the ENS. We confirmed VZV infection of the gut in latently infected adults and demonstrated that SVV DNA was similarly present in gut of monkeys latently infected with SVV using quantitative real-time PCR. In situ analyses showed that enteric neurons expressed SVV open reading frame (ORF) 63 RNA, but not viral nucleocapsid proteins, suggestive of latent ENS infection. During primary infection, SVV-infected T-cells were detected in gut-draining mesenteric lymph nodes and located in close vicinity to enteric nerves in the gut. Furthermore, flow cytometric analysis of blood from acutely SVV-infected monkeys demonstrated that Virus-infected T-cells expressed the gut-homing receptor α4β7 integrin. Collectively, the data demonstrate that SVV infects ENS neurons during primary infection and supports the role of T-cells in Virus dissemination to the gut. Because SVV reactivation can be experimentally induced, the SVV nonhuman primate model holds great potential to study the pathogenesis of enteric zoster.

Kenneth F. Soike - One of the best experts on this subject based on the ideXlab platform.

  • viral gene expression during acute Simian Varicella Virus infection
    Journal of General Virology, 2002
    Co-Authors: Wayne L Gray, Lisa Mullis, Kenneth F. Soike
    Abstract:

    Simian Varicella Virus (SVV) causes a natural Varicella-like disease in nonhuman primates. Outbreaks of Simian Varicella occur sporadically in primate facilities. Simian Varicella is used as a model for investigation of Varicella-zoster Virus (VZV) pathogenesis and latency. In this study, SVV gene expression and histopathology were analysed in tissues of acutely infected vervet monkeys. RT–PCR analysis demonstrated expression of specific SVV immediate early, early and late genes in the skin, lung, liver and ganglia tissues of acutely infected monkeys. Viral antigen expression and histopathology, including necrosis and inflammation, were detected in the skin, lungs, liver and spleen of infected monkeys by immunohistochemical analysis. Viral antigen expression, but little or no histopathology, was evident in the neural ganglia, the eventual site of viral latency. The study provides a foundation for further investigation on the role of viral genes in Varicella pathogenesis and latency.

  • Simian Varicella Virus infects ganglia before rash in experimentally infected monkeys
    Virology, 2001
    Co-Authors: Ravi Mahalingam, Mary Wellish, Tiffany M. White, Kenneth F. Soike, B K Kleinschmidtdemasters, Donald H. Gilden
    Abstract:

    Abstract Monkeys experimentally infected with Simian Varicella Virus (SVV) develop rash 10–14 days later. However, the route and the time of ganglionic infection are unknown. Using PCR, we analyzed DNA extracted from tissues of 13 monkeys 5 to 60 days after either intratracheal or intravenous inoculation with SVV. SVV DNA was detected in ganglia from four of five monkeys sacrificed 6 to 7 days after intratracheal inoculation. Further, analysis of ganglia from monkeys sacrificed at 10 days revealed that intravenous inoculation produced a higher proportion of SVV DNA-positive ganglia (63%) than that after intratracheal inoculation (13%), pointing to the role of hematogenous spread in ganglionic infection. Like other organs, monkey ganglia become infected with SVV before the appearance of rash.

  • sequence analysis of the leftward end of Simian Varicella Virus ecori i fragment reveals the presence of an 8 bp repeat flanking the unique long segment and an 881 bp open reading frame that is absent in the Varicella zoster Virus genome
    Virology, 2000
    Co-Authors: Ravi Mahalingam, Donald H. Gilden, Mary Wellish, Tiffany M. White, Kenneth F. Soike, Wayne L Gray
    Abstract:

    Simian Varicella Virus (SVV) causes Varicella (chickenpox) in nonhuman primates, becomes latent in cranial and dorsal root ganglia, and reactivates to produce zoster (shingles). Because the clinical and molecular features of SVV closely resemble those of Varicella zoster Virus (VZV) infection of humans, SVV infection of primates has served as an experimental model of VZV pathogenesis and latency. The SVV genome has been completely mapped, but attempts to clone the 3600-bp EcoRI fragment located at the leftward end of the Virus genome have hitherto been unsuccessful. Herein, we report the cloning and the complete nucleotide sequence of this region. Comparison of the SVV and VZV sequences in this region revealed an 8-bp inverted repeat sequence flanking the unique long segment of the SVV genome; an 879-bp open-reading frame (ORF) A in SVV that is absent in VZV but has 42% amino acid identity to SVV ORF 4 and 49% to VZV ORF 4; a 342-bp ORF B in SVV with 35% amino acid identity to a 387-bp ORF located to the left of ORF 1 on the VZV genome; and a 303-bp ORF in SVV with 27% amino acid identity to VZV ORF 1. No homologue of VZV ORF 2 was detected. Transcripts specific for ORFs A and B were present in SVV-infected cells in culture and in acutely infected monkey ganglia. Overall, there are more than 2000 bp of DNA in the SVV genome that are absent in the VZV genome.

  • infectious Simian Varicella Virus expressing the green fluorescent protein
    Journal of NeuroVirology, 1998
    Co-Authors: Ravi Mahalingam, Mary Wellish, Tiffany M. White, Kenneth F. Soike, Randall J Cohrs, B K Kleinschmidtdemasters, Donald H. Gilden
    Abstract:

    Clinical, pathologic, immunologic and virologic features of Simian Varicella Virus (SVV) infection in primates closely resemble Varicella-zoster Virus (VZV) infection in humans. Such similarities provide a rationale to analyze SVV infection in primates as a model of Varicella pathogenesis and latency. Thus, we constructed an SVV-expressing green fluorescent protein (SVV-GFP) by inserting the GFP gene into the unique short segment of the Virus genome by homologous recombination. Analysis of recombinant viral DNA and the expressed proteins of plaque-purified SVV-GFP confirmed the location of the GFP insert and that the recombinant SVV expressed the 27 kDa GFP. Infection of monkey kidney cells in tissue culture with SVV-GFP revealed bright green fluorescence associated with the characteristic focal cytopathic effect produced by SVV infection. Microscopic examination of lung from a 3-month-old African green monkey 10 days after infection with SVV-GFP revealed bright green fluorescence in areas of acute necrot...

  • experimental Simian Varicella Virus infection of st kitts vervet monkeys
    Journal of Medical Primatology, 1998
    Co-Authors: Wayne L Gray, Rhonda J Williams, Ruixin Chang, Kenneth F. Soike
    Abstract:

    Experimental Simian Varicella Virus (SVV) infection of St. Kitts vervet monkeys was evaluated as an animal model to investigate human Varicella-zoster Virus (VZV) infections. During the incubation period, viremia disseminated infectious Virus throughout the body via infected peripheral blood lymphocytes (PBLs). A vesicular skin rash in the inguinal area, and on the abdomen, extremities, and face appeared on day 7-10 postinfection. Necrosis and hemorrhage in lung and liver tissues from acutely infected monkeys were evident upon histologic analysis. Recovery from Simian Varicella was accompanied by a rise in the serum neutralizing antibody response to the Virus. SVV latency was established in trigeminal ganglia of monkeys which resolved the acute infection. This study indicates that experimental SVV infection of St. Kitts vervets is a useful animal model to investigate SVV and VZV pathogenesis and to evaluate potential antiviral agents and vaccines.

Ilhem Messaoudi - One of the best experts on this subject based on the ideXlab platform.

  • current in vivo models of Varicella zoster Virus neurotropism
    Viruses, 2019
    Co-Authors: Ravi Mahalingam, Leigh Zerboni, Wayne L Gray, Ilhem Messaoudi, Michael D. Gershon, Anne A. Gershon, Ann M. Arvin, Jeffrey I Cohen, Vicki Trainadorge
    Abstract:

    Varicella-zoster Virus (VZV), an exclusively human herpesVirus, causes chickenpox and establishes a latent infection in ganglia, reactivating decades later to produce zoster and associated neurological complications. An understanding of VZV neurotropism in humans has long been hampered by the lack of an adequate animal model. For example, experimental inoculation of VZV in small animals including guinea pigs and cotton rats results in the infection of ganglia but not a rash. The severe combined immune deficient human (SCID-hu) model allows the study of VZV neurotropism for human neural sub-populations. Simian Varicella Virus (SVV) infection of rhesus macaques (RM) closely resembles both human primary VZV infection and reactivation, with analyses at early times after infection providing valuable information about the extent of viral replication and the host immune responses. Indeed, a critical role for CD4 T-cell immunity during acute SVV infection as well as reactivation has emerged based on studies using RM. Herein we discuss the results of efforts from different groups to establish an animal model of VZV neurotropism.

  • Varicella Virus host interactions during latency and reactivation lessons from Simian Varicella Virus
    Frontiers in Microbiology, 2018
    Co-Authors: Oceane Sorel, Ilhem Messaoudi
    Abstract:

    Varicella zoster Virus (VZV) is a neurotropic alphaherpesVirus and the causative agent of Varicella (chickenpox) in humans. Following primary infection, VZV establishes latency in the sensory ganglia and can reactivate to cause herpes zoster, more commonly known as shingles, which causes significant morbidity, and on rare occasions mortality, in the elderly. Because VZV infection is highly restricted to humans, the development of a reliable animal model has been challenging, and our understanding of VZV pathogenesis remains incomplete. As an alternative, infection of rhesus macaques with the homologous Simian Varicella Virus (SVV) recapitulates the hallmarks of VZV infection and thus constitutes a robust animal model to provide critical insights into VZV pathogenesis and the host antiviral response. In this model, SVV infection results in the development of Varicella during primary infection, generation of an adaptive immune response, establishment of latency in the sensory ganglia, and viral reactivation upon immune suppression. In this review, we discuss our current knowledge about host and viral factors involved in the establishment of SVV latency and reactivation as well as the important role played by T cells in SVV pathogenesis and antiviral immunity.

  • Robust gene expression changes in the ganglia following subclinical reactivation in rhesus macaques infected with Simian Varicella Virus
    Journal of NeuroVirology, 2017
    Co-Authors: Nicole Arnold, Christine Meyer, Flora Engelmann, Ilhem Messaoudi
    Abstract:

    Varicella zoster Virus (VZV) causes Varicella during acute infection and establishes latency in the sensory ganglia. Reactivation of VZV results in herpes zoster, a debilitating and painful disease. It is believed that VZV reactivates due to a decline in cell-mediated immunity; however, the roles that CD4 versus CD8 T cells play in the prevention of herpes zoster remain poorly understood. To address this question, we used a well-characterized model of VZV infection where rhesus macaques are intrabronchially infected with the homologous Simian Varicella Virus (SVV). Latently infected rhesus macaques were thymectomized and depleted of either CD4 or CD8 T cells to induce selective senescence of each T cell subset. After T cell depletion, the animals were transferred to a new housing room to induce stress. SVV reactivation (viremia in the absence of rash) was detected in three out of six CD8-depleted and two out of six CD4-depleted animals suggesting that both CD4 and CD8 T cells play a critical role in preventing SVV reactivation. Viral loads in multiple ganglia were higher in reactivated animals compared to non-reactivated animals. In addition, reactivation results in sustained transcriptional changes in the ganglia that enriched to gene ontology and diseases terms associated with neuronal function and inflammation indicative of potential damage as a result of viral reactivation. These studies support the critical role of cellular immunity in preventing Varicella Virus reactivation and indicate that reactivation results in long-lasting remodeling of the ganglia transcriptome.

  • Simian Varicella Virus causes robust transcriptional changes in t cells that support viral replication
    Virus Research, 2017
    Co-Authors: Nicole Arnold, Ilhem Messaoudi
    Abstract:

    Varicella zoster Virus (VZV) causes Varicella (chickenpox) during acute infection. Several studies have shown that T cells are early and preferential targets of VZV infection that play a critical role in disseminating VZV in to the skin and ganglia. However, the transcriptional changes that occur in VZV-infected T cells remain unclear due to limited access to clinical samples and robust translational animal models. In this study, we used a nonhuman primate model of VZV infection where rhesus macaques are infected with the closely related Simian Varicella Virus (SVV) to provide novel insights into VZV-T cell interactions. RNA sequencing of bronchial alveolar lavage-resident T cells isolated from infected rhesus macaques show that SVV infection alters expression of genes important for regulation of gene expression, cell cycle progression, metabolism, and antiviral immunity. These data provide insight into cellular processes that may support viral replication, facilitate SVV dissemination, and evade host defense.

  • acute Simian Varicella Virus infection causes robust and sustained changes in gene expression in the sensory ganglia
    Journal of Virology, 2016
    Co-Authors: Nicole Arnold, Thomas Girke, Suhas Sureshchandra, Ilhem Messaoudi
    Abstract:

    ABSTRACT 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. IMPORTANCE Many 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.