scholarly journals Virus–Host Interplay Between Poly (ADP-Ribose) Polymerase 1 and Oncogenic Gammaherpesviruses

2022 ◽  
Vol 12 ◽  
Author(s):  
Woo-Chang Chung ◽  
Moon Jung Song
Keyword(s):  
Life Cycle ◽  
Lytic Replication ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Virus Life Cycle ◽  
Damage Response ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68 ◽  
Adp Ribosyltransferase

The gammaherpesviruses, include the Epstein–Barr virus, Kaposi’s sarcoma-associated herpesvirus, and murine gammaherpesvirus 68. They establish latent infection in the B lymphocytes and are associated with various lymphoproliferative diseases and tumors. The poly (ADP-ribose) polymerase-1 (PARP1), also called ADP-ribosyltransferase diphtheria-toxin-like 1 (ARTD1) is a nuclear enzyme that catalyzes the transfer of the ADP-ribose moiety to its target proteins and participates in important cellular activities, such as the DNA-damage response, cell death, transcription, chromatin remodeling, and inflammation. In gammaherpesvirus infection, PARP1 acts as a key regulator of the virus life cycle: lytic replication and latency. These viruses also develop various strategies to regulate PARP1, facilitating their replication. This review summarizes the roles of PARP1 in the viral life cycle as well as the viral modulation of host PARP1 activity and discusses the implications. Understanding the interactions between the PARP1 and oncogenic gammaherpesviruses may lead to the identification of effective therapeutic targets for the associated diseases.

scholarly journals The Murine Gammaherpesvirus 68 ORF27 Gene Product Contributes to Intercellular Viral Spread

2005 ◽  
Vol 79 (8) ◽  
pp. 5059-5068 ◽  
Author(s):  
Janet S. May ◽  
Jennifer Walker ◽  
Susanna Colaco ◽  
Philip G. Stevenson
Keyword(s):  
Gene Product ◽  
Lytic Replication ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Viral Spread ◽  
Virion Release ◽  
Direct Spread ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Herpesviruses remain predominantly cell associated within their hosts, implying that they spread between cells by a mechanism distinct from free virion release. We previously identified the efficient release of murine gammaherpesvirus 68 (MHV-68) virions as a function of the viral gp150 protein. Here we show that the MHV-68 ORF27 gene product, gp48, contributes to the direct spread of viruses from lytically infected to uninfected cells. Monoclonal antibodies to gp48 identified it on infected cell surfaces and in virions. gp48-deficient viruses showed no obvious deficit in virion cell binding, single-cycle replication, or virion release but had reduced lytic propagation between cells. After intranasal infection of mice, ORF27-deficient viruses were impaired predominantly in lytic replication in the lungs. There was a small deficit in latency establishment, but long-term latency appeared normal. Since ORF27 has homologs in both Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus, it is likely part of a conserved mechanism employed by gammaherpesviruses to disseminate lytically in their hosts.

scholarly journals Selective Uptake of Small RNA Molecules in the Virion of Murine Gammaherpesvirus 68

2008 ◽  
Vol 83 (5) ◽  
pp. 2321-2326 ◽  
Author(s):  
Anna R. Cliffe ◽  
Anthony A. Nash ◽  
Bernadette M. Dutia
Keyword(s):  
Small Rna ◽  
Nuclear Staining ◽  
Rna Molecules ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Genes Encoding ◽  
Infected Cells ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Noncoding RNAs are a feature of many herpesvirus genomes. They include microRNAs, whose function is the subject of intense investigation, in addition to longer RNA molecules such as the Epstein-Barr virus-encoded RNAs and herpesvirus saimiri U RNAs, which have been known for some time but whose function is still not well defined. Murine gammaherpesvirus 68 (MHV-68) encodes eight viral tRNA-like molecules (vtRNAs) of unknown function. Investigating the kinetics of expression of the vtRNAs, we observed that they were present directly after infection with the virus. This strongly suggested that vtRNAs were part of the virion structure, which was confirmed by their detection within various purified, RNase-treated preparations. Although both viral and cellular mRNAs were also detected within the MHV-68 virion, the major RNA species present were small RNAs of around 70 nucleotides in length. Interestingly, incorporation of viral mRNA was not related to the relative abundance in infected cells, as M11 mRNA, which is present at low abundance, was found in virions. MHV-76, which lacks the genes encoding the vtRNAs, also incorporated small RNA molecules within the virion, suggesting a requirement for these molecules for virion maturation. In productively infected cells the vtRNAs localized predominantly within the cytoplasm, although they also exhibited a globular pattern of nuclear staining. Their presence in the cytoplasm is consistent with interaction with virion components prior to maturation of virus particles. The significance of these findings for virion architecture and function is discussed.

scholarly journals Identification of Novel Rodent Herpesviruses, Including the First Gammaherpesvirus of Mus musculus

2007 ◽  
Vol 81 (15) ◽  
pp. 8091-8100 ◽  
Author(s):  
Bernhard Ehlers ◽  
Judit Küchler ◽  
Nezlisah Yasmum ◽  
Güzin Dural ◽  
Sebastian Voigt ◽  
...  
Keyword(s):  
Mus Musculus ◽  
Human Herpesvirus ◽  
Murine Cytomegalovirus ◽  
Long Distance ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68 ◽  
Pcr Targeting

ABSTRACT Rodent herpesviruses such as murine cytomegalovirus (host, Mus musculus), rat cytomegalovirus (host, Rattus norvegicus), and murine gammaherpesvirus 68 (hosts, Apodemus species) are important tools for the experimental study of human herpesvirus diseases. However, alphaherpesviruses, roseoloviruses, and lymphocryptoviruses, as well as rhadinoviruses, that naturally infect Mus musculus (house mouse) and other Old World mice are unknown. To identify hitherto-unknown rodent-associated herpesviruses, we captured M. musculus, R. norvegicus, and 14 other rodent species in several locations in Germany, the United Kingdom, and Thailand. Samples of trigeminal ganglia, dorsal root ganglia, brains, spleens, and other organs, as well as blood, were analyzed with a degenerate panherpesvirus PCR targeting the DNA polymerase (DPOL) gene. Herpesvirus-positive samples were subjected to a second degenerate PCR targeting the glycoprotein B (gB) gene. The sequences located between the partial DPOL and gB sequences were amplified by long-distance PCR and sequenced, resulting in a contiguous sequence of approximately 3.5 kbp. By DPOL PCR, we detected 17 novel betaherpesviruses and 21 novel gammaherpesviruses but no alphaherpesvirus. Of these 38 novel herpesviruses, 14 were successfully analyzed by the complete bigenic approach. Most importantly, the first gammaherpesvirus of Mus musculus was discovered (Mus musculus rhadinovirus 1 [MmusRHV1]). This virus is a member of a novel group of rodent gammaherpesviruses, which is clearly distinct from murine herpesvirus 68-like rodent gammaherpesviruses. Multigenic phylogenetic analysis, using an 8-kbp locus, revealed that MmusRHV1 diverged from the other gammaherpesviruses soon after the evolutionary separation of Epstein-Barr virus-like lymphocryptoviruses from human herpesvirus 8-like rhadinoviruses and alcelaphine herpesvirus 1-like macaviruses.

scholarly journals Host Shutoff Is a Conserved Phenotype of Gammaherpesvirus Infection and Is Orchestrated Exclusively from the Cytoplasm

2009 ◽  
Vol 83 (18) ◽  
pp. 9554-9566 ◽  
Author(s):  
Sergio Covarrubias ◽  
Justin M. Richner ◽  
Karen Clyde ◽  
Yeon J. Lee ◽  
Britt A. Glaunsinger
Keyword(s):  
Murine Gammaherpesvirus ◽  
Functional Conservation ◽  
Barr Virus ◽  
Infected Cells ◽  
Host Shutoff ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68 ◽  
Cellular Transcriptome

ABSTRACT Lytic infection with the two human gammaherpesviruses, Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV), leads to significant depletion of the cellular transcriptome. This host shutoff phenotype is driven by the conserved herpesviral alkaline exonuclease, termed SOX in KSHV and BGLF5 in EBV, which in gammaherpesviruses has evolved the genetically separable ability to target cellular mRNA. We now show that host shutoff is also a prominent consequence of murine gammaherpesvirus 68 (MHV68) infection, which is widely used as a model system to study pathogenesis of these viruses in vivo. The effector of MHV68-induced host shutoff is its SOX homolog, here termed muSOX. There is remarkable functional conservation of muSOX host shutoff activities with those of KSHV SOX, including the recently described ability of SOX to induce mRNA hyperadenylation in the nucleus as well as cause nuclear relocalization of the poly(A) binding protein. SOX and muSOX localize to both the nucleus and cytoplasm of infected cells. Using spatially restricted variants of these proteins, we go on to demonstrate that all known host shutoff-related activities of SOX and muSOX are orchestrated exclusively from the cytoplasm. These results have important mechanistic implications for how SOX and muSOX target nascent cellular transcripts in the nucleus. Furthermore, our findings establish MHV68 as a new, genetically tractable model to study host shutoff.

scholarly journals Infection of neonates with murine gammaherpesvirus 68 results in enhanced viral persistence in lungs and absence of infectious mononucleosis syndrome

2008 ◽  
Vol 89 (5) ◽  
pp. 1114-1121 ◽  
Author(s):  
Catherine Ptaschinski ◽  
Rosemary Rochford
Keyword(s):  
T Cell ◽  
Infectious Mononucleosis ◽  
Acute Infection ◽  
Viral Dna ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Age Dependent ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

We used the murine gammaherpesvirus 68 (γHV-68), which serves as a model for human gammaherpesvirus infection, to determine whether age at infection altered the pattern of gammaherpesvirus pathogenesis. We infected mice intranasally at 8 days old (pups) and 6 weeks old (adults) to investigate differences in γHV-68 pathogenesis. There was no difference between adults or pups in acute infection in the lungs at 6 days post-infection (p.i.). However, mice infected as pups exhibited a more disseminated viral infection with viral DNA detected in the spleen, liver and heart as measured by quantitative PCR (Q-PCR). In addition, viral DNA was detected in the lungs of mice infected as pups until 60 days p.i. Three viral transcripts (M2, M3 and M9) were expressed at both 30 and 60 days p.i. In contrast, no viral DNA or mRNA expression was detected in lungs of mice infected as adults at 30 or 60 days p.i. Mice infected as adults experienced a peak in latent infection in the spleen at 16 days p.i., corresponding with an increase in splenic weight and expansion of the Vβ4+ CD8+ T-cell population, similar to infectious mononucleosis observed following infection of young adults with Epstein–Barr virus. However, the increase in splenic weight of infected pups was not as pronounced and no significant increase in Vβ4+ CD8+ T-cell expansion was observed in infected pups. Together, these data suggest that the pathogenesis of murine gammaherpesvirus γHV-68 is age-dependent.

scholarly journals A Gammaherpesvirus Noncoding RNA Is Essential for Hematogenous Dissemination and Establishment of Peripheral Latency

mSphere ◽  
2016 ◽  
Vol 1 (2) ◽  
Author(s):  
Emily R. Feldman ◽  
Mehmet Kara ◽  
Lauren M. Oko ◽  
Katrina R. Grau ◽  
Brian J. Krueger ◽  
...  
Keyword(s):  
Kaposi's Sarcoma ◽  
Kaposi’S Sarcoma ◽  
Hematogenous Dissemination ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Regulatory Rnas ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Noncoding RNAs (ncRNAs) represent an intriguing and diverse class of molecules that are now recognized for their participation in a wide array of cellular processes. Viruses from multiple families have evolved to encode their own such regulatory RNAs; however, the specific in vivo functions of these ncRNAs are largely unknown. Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) are ubiquitous human pathogens that are associated with the development of numerous malignancies. Like EBV and KSHV, murine gammaherpesvirus 68 (MHV68) establishes lifelong latency in B cells and is associated with lymphomagenesis. The work described here reveals that the MHV68 ncRNA TMER4 acts at a critical bottleneck in local lymph nodes to facilitate hematogenous dissemination of the virus and establishment of latency at peripheral sites. Recent intense investigations have uncovered important functions for a diverse array of novel noncoding RNA (ncRNA) species, including microRNAs (miRNAs) and long noncoding RNAs. Not surprisingly, viruses from multiple families have evolved to encode their own regulatory RNAs; however, the specific in vivo functions of these ncRNAs are largely unknown. The human gammaherpesviruses Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) are highly ubiquitous pathogens that are associated with the development of a wide range of malignancies, including Burkitt’s lymphoma, Hodgkin’s lymphoma, nasopharyngeal carcinoma, and Kaposi’s sarcoma. Like EBV and KSHV, murine gammaherpesvirus 68 (MHV68) establishes lifelong latency in B cells and is associated with lymphoproliferative disease and lymphoma. Similar to the EBV-encoded small RNA (EBER)-1 and -2, MHV68 encodes eight 200- to 250-nucleotide polymerase III-transcribed ncRNAs called TMERs (tRNA-miRNA-encoded RNAs), which are highly expressed in latently infected cells and lymphoproliferative disease. To define the in vivo contribution of TMERs to MHV68 biology, we generated a panel of individual TMER mutant viruses. Through comprehensive in vivo analyses, we identified TMER4 as a key mediator of virus dissemination. The TMER4 mutant virus replicated normally in lungs and spread with normal kinetics and distribution to lung-draining lymph nodes, but it was significantly attenuated for infection of circulating blood cells and for latency establishment at peripheral sites. Notably, TMER4 stem-loops but not miRNAs were essential for wild-type TMER4 activity. Thus, these findings revealed a crucial miRNA-independent function of the TMER4 ncRNA in MHV68 hematogenous dissemination and latency establishment. IMPORTANCE Noncoding RNAs (ncRNAs) represent an intriguing and diverse class of molecules that are now recognized for their participation in a wide array of cellular processes. Viruses from multiple families have evolved to encode their own such regulatory RNAs; however, the specific in vivo functions of these ncRNAs are largely unknown. Epstein-Barr virus (EBV) and Kaposi’s sarcoma-associated herpesvirus (KSHV) are ubiquitous human pathogens that are associated with the development of numerous malignancies. Like EBV and KSHV, murine gammaherpesvirus 68 (MHV68) establishes lifelong latency in B cells and is associated with lymphomagenesis. The work described here reveals that the MHV68 ncRNA TMER4 acts at a critical bottleneck in local lymph nodes to facilitate hematogenous dissemination of the virus and establishment of latency at peripheral sites. Podcast: A podcast concerning this article is available.

scholarly journals Induction of Protective Immunity against Murine Gammaherpesvirus 68 Infection in the Absence of Viral Latency

2009 ◽  
Vol 84 (5) ◽  
pp. 2453-2465 ◽  
Author(s):  
Qingmei Jia ◽  
Michael L. Freeman ◽  
Eric J. Yager ◽  
Ian McHardy ◽  
Leming Tong ◽  
...  
Keyword(s):  
Human Herpesvirus ◽  
Lytic Replication ◽  
Wild Type Virus ◽  
Wild Type ◽  
Transcription Activator ◽  
Vaccine Strategy ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

ABSTRACT Human gammaherpesviruses, Epstein-Barr virus, and human herpesvirus 8/Kaposi's sarcoma-associated herpesvirus are important pathogens associated with diseases, including lymphomas and other malignancies. Murine gammaherpesvirus 68 (MHV-68) is used as an experimental model system to study the host immune control of infection and explore novel vaccine strategies based on latency-deficient live viruses. We studied the properties and the potential of a recombinant MHV-68 (AC-RTA) in which the genes required for persistent infection were replaced by a constitutively expressed viral transcription activator, RTA, which dictates the virus to lytic replication. After intranasal infection of mice, replication of AC-RTA in the lung was attenuated, and no AC-RTA virus or viral DNA was detected in the isolated splenocytes, indicating a lack of latency in the spleen. Infection of the AC-RTA virus elicited both cellular immune responses and virus-specific IgG at a level comparable to that elicited by infection of the wild-type virus. Importantly, vaccination of AC-RTA was able to protect mice against subsequent challenge by the wild-type MHV-68. AC-RTA provides a vaccine strategy for preventing infection of human gammaherpesviruses. Furthermore, our results suggest that immunity to the major latent antigens is not required for protection.

scholarly journals Antiapoptotic Herpesvirus Bcl-2 Homologs Escape Caspase-Mediated Conversion to Proapoptotic Proteins

2000 ◽  
Vol 74 (11) ◽  
pp. 5024-5031 ◽  
Author(s):  
David S. Bellows ◽  
B. Nelson Chau ◽  
Percy Lee ◽  
Yuri Lazebnik ◽  
William H. Burns ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Apoptotic Cell ◽  
Caspase Cleavage ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Cell Extracts ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Herpesvirus 4 ◽  
Murine Gammaherpesvirus 68

ABSTRACT The antiapoptotic Bcl-2 and Bcl-xL proteins of mammals are converted into potent proapoptotic factors when they are cleaved by caspases, a family of apoptosis-inducing proteases (E. H.-Y. Cheng, D. G. Kirsch, R. J. Clem, R. Ravi, M. B. Kastan, A. Bedi, K. Ueno, and J. M. Hardwick, Science 278:1966–1968, 1997; R. J. Clem, E. H.-Y. Cheng, C. L. Karp, D. G. Kirsch, K. Ueno, A. Takahashi, M. B. Kastan, D. E. Griffin, W. C. Earnshaw, M. A. Veliuona, and J. M. Hardwick, Proc. Natl. Acad. Sci. USA 95:554–559, 1998). Gamma herpesviruses also encode homologs of the Bcl-2 family. All tested herpesvirus Bcl-2 homologs possess antiapoptotic activity, including the more distantly related homologs encoded by murine gammaherpesvirus 68 (γHV68) and bovine herpesvirus 4 (BHV4), as described here. To determine if viral Bcl-2 proteins can be converted into death factors, similar to their cellular counterparts, five herpesvirus Bcl-2 homologs from five different viruses were tested for their susceptibility to caspases. Only the viral Bcl-2 protein encoded by γHV68 was susceptible to caspase digestion. However, unlike the caspase cleavage products of cellular Bcl-2, Bcl-xL, and Bid, which are potent inducers of apoptosis, the cleavage product of γHV68 Bcl-2 lacked proapoptotic activity. KSBcl-2, encoded by the Kaposi's sarcoma-associated herpesvirus, was the only viral Bcl-2 homolog that was capable of killing cells when expressed as an N-terminal truncation. However, because KSBcl-2 was not cleavable by caspases, the latent proapoptotic activity of KSBcl-2 apparently cannot be released. The Bcl-2 homologs encoded by herpesvirus saimiri, Epstein-Barr virus, and BHV4 were not cleaved by apoptotic cell extracts and did not possess latent proapoptotic activities. Thus, herpesvirus Bcl-2 homologs escape negative regulation by retaining their antiapoptotic activities and/or failing to be converted into proapoptotic proteins by caspases during programmed cell death.

scholarly journals Kinetic and phenotypic changes in murine lymphocytes infected with murine gammaherpesvirus-68 in vitro

1999 ◽  
Vol 80 (10) ◽  
pp. 2729-2736 ◽  
Author(s):  
Bernadette M. Dutia ◽  
James P. Stewart ◽  
Robert A. E. Clayton ◽  
Heather Dyson ◽  
Anthony A. Nash
Keyword(s):  
Epstein Barr Virus ◽  
Herpesvirus Saimiri ◽  
Murine Splenocytes ◽  
Murine Gammaherpesvirus ◽  
Barr Virus ◽  
Growth Transformation ◽  
Epstein Barr ◽  
Gammaherpesvirus 68 ◽  
Murine Gammaherpesvirus 68

Primary infection with murine gammaherpesvirus-68 (MHV-68), as with other members of the gammaherpesvirus subfamily, is characterized by a lymphoproliferative phase. MHV-68 causes acute splenomegaly and an infectious mononucleosis-like syndrome in which there is expansion of the CD8+ T cell subset. In long-term infections, MHV-68 is associated with lymphoma development. In order to elucidate the mechanisms underlying the proliferative processes, the events following infection of murine splenocytes or purified murine B lymphocytes in vitro have been examined. MHV-68 infection prolonged the viability of murine splenocytes and stimulated cellular proliferation. Unlike Epstein–Barr virus and herpesvirus saimiri, MHV-68 did not cause growth transformation. Growth transformation did not occur even when cells with a predisposition to transformation were infected or when culture conditions were selected to enhance the viability of the cells. Following MHV-68 infection, the latency-associated viral tRNAs were transcribed. However, transcription of the other known latency- associated gene, M2, was not observed. In addition, there was no evidence of productive virus replication either by staining with antibodies specific for late virus antigens or by in situ hybridization for early and late mRNAs. In contrast to Epstein–Barr virus- and herpesvirus saimiri-infected lymphocytes, where episomal genomes are seen, Gardella gel analysis indicated that the primary lymphocytes infected by MHV-68 in vitro contained only linear virus DNA. This DNA was nuclease sensitive, indicating that, while MHV-68 was efficiently uncoated, its circularization in vitro was extremely inefficient. These results are discussed in terms of the host–virus interaction.

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