Pathogenesis of a Model Gammaherpesvirus in a Natural Host

Hughes, David J.; Kipar, Anja; Sample, Jeffery T.; Stewart, James P.

doi:10.1128/jvi.02085-09

Cited by 42 publications

(70 citation statements)

References 48 publications

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“…Intracerebral injection of the same M3 mutant virus does lead to an altered inflammatory response, with higher numbers of infiltrating lymphocytes and macrophages than observed following inoculation with the wild-type virus (28). However, M3 contributes significantly to MHV68 pathogenesis in a natural host, wood mice, where lack of M3 resulted in substantially reduced latency in the spleen and lung (29,30).…”

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confidence: 98%

Rodent Herpesvirus Peru Encodes a Secreted Chemokine Decoy Receptor

Lubman

Cella

Wang

et al. 2014

J Virol

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Viruses have long been studied not only for their pathology and associated disease but also as model systems for understanding cellular and immunological processes. Rodent herpesvirus Peru (RHVP) is a recently characterized rhadinovirus related to murine gammaherpesvirus 68 (MHV68) and Kaposi's sarcoma-associated herpesvirus (KSHV) that establishes acute and latent infection in laboratory mice. RHVP encodes numerous unique proteins that we hypothesize might facilitate host immune evasion during infection. We report here that open reading frame (ORF) R17 encodes a high-affinity chemokine binding protein that broadly recognizes human and murine CC and C chemokines. The interaction of R17 with chemokines is generally characterized by rapid association kinetics, and in the case of CCL3, CCL4, CCL5, CCL24, and XCL1, extremely stable complexes are formed. Functionally, R17 potently inhibited CCL2-driven chemotaxis of the human monocytic cell line THP-1, CCL3-driven chemotaxis of peripheral blood mononuclear cells, and CCL2-mediated calcium flux. Our studies also reveal that R17 binds to glycosaminoglycans (GAGs) in a process dependent upon two BBXB motifs and that chemokine and GAG binding can occur simultaneously at distinct sites. Collectively, these studies suggest that R17 may play a role in RHVP immune evasion through the targeted sabotage of chemokine-mediated immune surveillance.

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confidence: 98%

Rodent Herpesvirus Peru Encodes a Secreted Chemokine Decoy Receptor

Lubman

Cella

Wang

et al. 2014

J Virol

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“…Besides MHV-72, several other murine herpesviruses were found occurring throughout some mouse species, which display similar pathogenesis of acute and latent infection manifested in their hosts. Among these is the Wood mouse herpesvirus isolated from wood mouse in the UK, the full genome sequence of which was recently identifi ed by Hughes et al (2010). Biological properties of some other murine herpesviruses (MHV-60, MHV-78, MHV-76, MHV-Šumava, MHV-4556) isolated from bank vole and wood mice in Slovakia and Bohemia (Blaškovič et al, 1980;Kožuch et al, 1993;Blaškovičová et al, 2007;Halásová et al, 2011;Kúdelová et al, 2012) are also studied (reviewed by Wagnerová et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Soluble M3 proteins of murine gammaherpesviruses 68 and 72 expressed in Escherichia coli: analysis of chemokine-binding properties

Matuskova¹,

Pančík²,

Štibrániová³

et al. 2015

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Summary. -M3 protein of murine gammaherpesvirus 68 (MHV-68) was identifi ed as a viral chemokinebinding protein 3 (vCKBP-3) capable to bind a broad spectrum of chemokines and their receptors. During both acute and latent infection MHV-68 M3 protein provides a selective advantage for the virus by inhibiting the antiviral and infl ammatory response. A unique mutation Asp307Gly was identifi ed in the M3 protein of murine gammaherpesvirus 72 (MHV-72), localized near chemokine-binding domain. Study on chemokine-binding properties of MHV-72 M3 protein purifi ed from medium of infected cells implied reduced binding to some chemokines when compared to MHV-68 M3 protein. It was suggested that the mutation in the M3 protein might be involved in the attenuation of immune response to infection with MHV-72. Recently, Escherichia coli cells were used to prepare native recombinant M3 proteins of murine gammaherpesviruses 68 and 72 (Pančík et al., 2013). In this study, we assessed the chemokine-binding properties of three M3 proteins prepared in E. coli Rosetta-gami 2 (DE3) cells, the full length M3 protein of both MHV-68 and MHV-72 and MHV-68 M3 protein truncated in the signal sequence (the fi rst 24 aa). Th ey all displayed binding activity to human chemokines CCL5 (RANTES), CXCL8 (IL-8), and CCL3 (MIP-1α). Th e truncated MHV-68 M3 protein had more than twenty times reduced binding activity to CCL5, but only about fi ve and three times reduced binding to CXCL8 and CCL3 when compared to its full length counterpart. Binding of the full length MHV-72 M3 protein to all chemokines was reduced when compared to MHV-68 M3 protein. Its binding to CCL5 and CCL3 was reduced over ten and seven times. However, its binding to CXCL8 was only slightly reduced (64.8 vs 91.8%). Th ese data implied the signifi cance of the signal sequence and also of a single mutation (at aa 307) for effi cient M3 protein binding to some chemokines.

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“…7B), confirming the lower virus replication and antigen load in this group. However, despite these differences in amounts of infectious viruses, focal lymphocyte infiltrations with potential lymphatic follicle formation, previously described as inducible bronchus-associated lymphoid tissue (iBALT) (41,42), were visible in all the groups (Fig. 7C).…”

Section: Resultsmentioning

confidence: 99%

Deletion of Murid Herpesvirus 4 ORF63 Affects the Trafficking of Incoming Capsids toward the Nucleus

Latif

Machiels

Xiao

et al. 2016

J Virol

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Gammaherpesviruses are important human and animal pathogens. Despite the fact that they display the classical architecture of herpesviruses, the function of most of their structural proteins is still poorly defined. This is especially true for tegument proteins. Interestingly, a potential role in immune evasion has recently been proposed for the tegument protein encoded by Kaposi's sarcoma-associated herpesvirus open reading frame 63 (ORF63). To gain insight about the roles of ORF63 in the life cycle of a gammaherpesvirus, we generated null mutations in the ORF63 gene of murid herpesvirus 4 (MuHV-4). We showed that disruption of ORF63 was associated with a severe MuHV-4 growth deficit both in vitro and in vivo. The latter deficit was mainly associated with a defect of replication in the lung but did not affect the establishment of latency in the spleen. From a functional point of view, inhibition of caspase-1 or the inflammasome did not restore the growth of the ORF63-deficient mutant, suggesting that the observed deficit was not associated with the immune evasion mechanism identified previously. Moreover, this growth deficit was also not associated with a defect in virion egress from the infected cells. In contrast, it appeared that MuHV-4 ORF63-deficient mutants failed to address most of their capsids to the nucleus during entry into the host cell, suggesting that ORF63 plays a role in capsid movement. In the future, ORF63 could therefore be considered a target to block gammaherpesvirus infection at a very early stage of the infection. IMPORTANCEThe important diseases caused by gammaherpesviruses in human and animal populations justify a better understanding of their life cycle. In particular, the role of most of their tegument proteins is still largely unknown. In this study, we used murid herpesvirus 4, a gammaherpesvirus infecting mice, to decipher the role of the protein encoded by the viral ORF63 gene. We showed that the absence of this protein is associated with a severe growth deficit both in vitro and in vivo that was mainly due to impaired migration of viral capsids toward the nucleus during entry. Together, our results provide new insights about the life cycle of gammaherpesviruses and could allow the development of new antiviral strategies aimed at blocking gammaherpesvirus infection at the very early stages. G ammaherpesviruses (␥HVs) are widespread viruses that cause lifelong infections in many mammalian species (1) and represent a significant cause of diseases (2, 3). Epstein-Barr virus (EBV; genus Lymphocryptovirus) and Kaposi's sarcoma-associated herpesvirus (KSHV; genus Rhadinovirus genus) are highly prevalent in human populations (3, 4) and are associated with several cancers (5). Despite the burden associated with these infections in some regions of the world, there is still no standard treatment (6). A better understanding of their biological cycle is therefore needed to develop new prophylactic or therapeutic strategies. As EBV and KSHV replicate poorly in vitro and have no establi...

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Pathogenesis of a Model Gammaherpesvirus in a Natural Host

Cited by 42 publications

References 48 publications

Rodent Herpesvirus Peru Encodes a Secreted Chemokine Decoy Receptor

Rodent Herpesvirus Peru Encodes a Secreted Chemokine Decoy Receptor

Soluble M3 proteins of murine gammaherpesviruses 68 and 72 expressed in Escherichia coli: analysis of chemokine-binding properties

Deletion of Murid Herpesvirus 4 ORF63 Affects the Trafficking of Incoming Capsids toward the Nucleus

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