Persistent Gammaherpesvirus Replication and Dynamic Interaction with the Host In Vivo

Hwang, Seungmin; Wu, Ting-Ting; Tong, Lili; Kim, Kyeong Seon; Martinez-Guzman, DeeAnn; Colantonio, Arnaud D.; Uíttenbogaart, Christel H.; Sun, Ren

doi:10.1128/jvi.01152-08

Cited by 78 publications

(102 citation statements)

References 55 publications

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“…Individual ISGs were screened for their antiviral effect on MHV-68 coexpressing a luciferase reporter with the early-late gene, M3 (MHV-68-Luc) (10). HEK293T cells were transfected in quadruplicate with individual ISGs for 36 h and infected with MHV-68-Luc for 9 h, which was about the linear range for luciferase expression after infection.…”

Section: Resultsmentioning

confidence: 99%

Systematic identification of type I and type II interferon-induced antiviral factors

Liu

Sanchez

Aliyari

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

409

377

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Type I and type II interferons (IFNs) are cytokines that establish the cellular antiviral state through the induction of IFN-stimulated genes (ISGs). We sought to understand the basis of the antiviral activity induced by type I and II IFNs in relation to the functions of their ISGs. Based on gene expression studies, we systematically identified antiviral ISGs by performing blinded, functional screens on 288 type I and type II ISGs. We assessed and validated the antiviral activity of these ISGs against an RNA virus, vesicular stomatitis virus (VSV), and a DNA virus, murine gammaherpes virus (MHV-68). Overall, we identified 34 ISGs that elicited an antiviral effect on the replication of either one or both viruses. Fourteen ISGs have uncharacterized antiviral functions. We further defined ISGs that affect critical life-cycle processes in expression of VSV protein and MHV-68 immediate-early genes. Two previously undescribed antiviral ISGs, TAP1 and BMP2, were further validated. TAP1-deficient fibroblasts were more susceptible to VSV infection but less so to MHV-68 infection. On the other hand, exogenous BMP2 inhibits MHV-68 lytic growth but did not affect VSV growth. These results delineate common and distinct sets of type I and type II IFN-induced genes as well as identify unique ISGs that have either broad or specific antiviral effects on these viruses.

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Section: Resultsmentioning

confidence: 99%

Systematic identification of type I and type II interferon-induced antiviral factors

Liu

Sanchez

Aliyari

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

409

377

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“…So far, it cannot be avoided that the genetic modification of the viral genome has subtle effects on the fitness of the resulting viruses and/or on the expression of any inserted gene (5,23,24,41). This problem was already observed in previous studies with MHV-68 using a fluorescent protein of the EGFP family (e.g., yellow fluorescent protein) to mark a virus in vivo (41).…”

Section: Discussionmentioning

confidence: 99%

“…MHV-68 is closely related to the two human gammaherpesviruses, Epstein-Barr virus (EBV) and Kaposi's sarcoma-associated herpesvirus (KSHV). All three viruses present an analogous genomic structure (2,3), infect leukocytes and epithelial cells (4)(5)(6)(7)(8), and establish life-long latency in lymphocytes. Furthermore, mononucleosis is comparable in EBV and MHV-68 pathogenesis (7,9), and all three viruses induce malignancies (10)(11)(12).…”

mentioning

confidence: 99%

“…After 2 to 3 weeks, the acute infection becomes controlled. During the last period of acute infection, infection of B cells, macrophages, and dendritic cells (DC) in lymphoid organs advances and the latent phase of MHV-68 infection is established (4)(5)(6)(7)(8). B cells represent the major reservoir of latent virus in the spleen, independently of the chosen route of infection (8,13), while macrophages were described as the major reservoir of latency in the peritoneal cavity, at least after intraperitoneal infection (13).…”

mentioning

confidence: 99%

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Systemic and Local Infection Routes Govern Different Cellular Dissemination Pathways during Gammaherpesvirus InfectionIn Vivo

Vidy

Sacher

Adler

et al. 2013

J Virol

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bHuman gammaherpesviruses cause morbidity and mortality associated with infection and transformation of lymphoid and endothelial cells. Knowledge of cell types involved in virus dissemination from primary virus entry to virus latency is fundamental for the understanding of gammaherpesvirus pathogenesis. However, the inability to directly trace cell types with respect to virus dissemination pathways has prevented definitive conclusions regarding the relative contribution of individual cell types. Here, we describe that the route of infection affects gammaherpesvirus dissemination pathways. We constructed a recombinant murine gammaherpesvirus 68 (MHV-68) variant harboring a cassette which switches fluorescent markers in a Cre-dependent manner. Since the recombinant virus which was constructed on the wild-type background was attenuated, in this study we used an M1-deleted version, which infected mice with normal kinetics. Infection of Cre-transgenic mice with this convertible virus was used to estimate the quantitative contribution of defined cell types to virus productivity and dissemination during the acute phase of MHV-68 infection. In systemic infection, we found splenic vascular endothelial cells (EC) among the first and main cells to produce virus. After local infection, the contribution of EC to splenic virus production did not represent such early kinetics. However, at later time points, B cell-derived viruses dominated splenic productivity independently of systemic or local infection. Systemic versus local infection also governed the cell types involved in loading peritoneal exudate cells, leading to latency in F4/ 80-and CD11b-positive target cells. Systemic infection supported EC-driven dissemination, whereas local infection supported B cell-driven dissemination.

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“…Latent infections permit lifelong viral persistence through evasion of the host immune response. Re-activation of gammaherpesvirus lytic gene expression and virus production may be triggered by insult to the immune system (Hwang et al, 2008;Sunil-Chandra et al, 1994;Yarilin et al, 2004). …”

Section: Introductionmentioning

confidence: 99%

Murine gammaherpesvirus-68 (MHV-68) is not horizontally transmitted amongst laboratory mice by cage contact

Aligo

Brosnan

Walker

et al. 2014

Journal of Immunotoxicology

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Murine gammaherpesvirus-68 (MHV-68), a natural pathogen of mice, is being evaluated as a model of Epstein Barr Virus (EBV) infection for use in investigation of the effects of immunomodulatory therapy on herpesvirus pathogenesis in humans. Immunosuppressive agents are used for treatment of a variety of autoimmune diseases as well as for prevention of tissue rejection after organ transplantation and can result in recrudescence of latent herpesvirus infections. Prior to examination of MHV-68 as a suitable model for EBV, better characterization of the MHV-68 model was desirable. Characterization of the MHV-68 model involved development of assays for detecting virus and for demonstration of safety when present in murine colonies. Limited information is available in the literature regarding MHV-68 transmission, although recent reports indicate the virus is not horizontally spread in research facilities. To further determine transmission potential, immunocompetent and immunodeficient mice were infected with MHV-68 and co-habitated with naïve animals. Molecular pathology assays were developed to characterize the MHV-68 model and to determine viral transmission. Horizontal transmission of virus was not observed from infected animals to naïve cagemates after fluorescence microscopy assays and quantitative PCR (qPCR). Serologic analysis complemented these studies and was used as a method of monitoring infection amongst murine colonies. Overall, these findings demonstrate that MHV-68 infection can be controlled and monitored in murine research facilities, and the potential for unintentional infection is low.

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Persistent Gammaherpesvirus Replication and Dynamic Interaction with the Host In Vivo

Cited by 78 publications

References 55 publications

Systematic identification of type I and type II interferon-induced antiviral factors

Systematic identification of type I and type II interferon-induced antiviral factors

Systemic and Local Infection Routes Govern Different Cellular Dissemination Pathways during Gammaherpesvirus InfectionIn Vivo

Murine gammaherpesvirus-68 (MHV-68) is not horizontally transmitted amongst laboratory mice by cage contact

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