scholarly journals A Deubiquitinating Activity Is Conserved in the Large Tegument Protein of the Herpesviridae

2005 ◽  
Vol 79 (24) ◽  
pp. 15582-15585 ◽  
Author(s):  
Christian Schlieker ◽  
Gregory A. Korbel ◽  
Lisa M. Kattenhorn ◽  
Hidde L. Ploegh
Keyword(s):  
Epstein Barr Virus ◽  
Murine Cytomegalovirus ◽  
Tegument Protein ◽  
Herpes Simplex Virus 1 ◽  
Barr Virus ◽  
Essential Function ◽  
Epstein Barr ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The largest tegument protein of herpes simplex virus 1 (HSV-1), UL36, contains a novel deubiquitinating activity embedded in it. All members of the Herpesviridae contain a homologue of HSV-1 UL36, the N-terminal segments of which show perfect conservation of those residues implicated in catalysis. For murine cytomegalovirus and Epstein-Barr virus, chosen as representatives of the beta- and gammaherpesvirus subfamilies, respectively, we here show that the homologous modules indeed display deubiquitinating activity in vitro. The conservation of this activity throughout all subfamilies is indicative of an important, if not essential, function.

scholarly journals Stimulation of the Replication of ICP0-Null Mutant Herpes Simplex Virus 1 and pp71-Deficient Human Cytomegalovirus by Epstein-Barr Virus Tegument Protein BNRF1

2016 ◽  
Vol 90 (21) ◽  
pp. 9664-9673 ◽  
Author(s):  
Yongxu Lu ◽  
Anne Orr ◽  
Roger D. Everett
Keyword(s):  
Epstein Barr Virus ◽  
Nuclear Bodies ◽  
Regulatory Proteins ◽  
Tegument Protein ◽  
Null Mutant ◽  
Herpes Simplex Virus 1 ◽  
Barr Virus ◽  
Epstein Barr ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT It is now well established that several cellular proteins that are components of promyelocytic leukemia nuclear bodies (PML NBs, also known as ND10) have restrictive effects on herpesvirus infections that are countered by viral proteins that are either present in the virion particle or are expressed during the earliest stages of infection. For example, herpes simplex virus 1 (HSV-1) immediate early (IE) protein ICP0 overcomes the restrictive effects of PML-NB components PML, Sp100, hDaxx, and ATRX while human cytomegalovirus (HCMV) IE protein IE1 targets PML and Sp100, and its tegument protein pp71 targets hDaxx and ATRX. The functions of these viral regulatory proteins are in part interchangeable; thus, both IE1 and pp71 stimulate the replication of ICP0-null mutant HSV-1, while ICP0 increases plaque formation by pp71-deficient HCMV. Here, we extend these studies by examining proteins that are expressed by Epstein-Barr virus (EBV). We report that EBV tegument protein BNRF1, discovered by other investigators to target the hDaxx/ATRX complex, increases the replication of both ICP0-null mutant HSV-1 and pp71-deficient HCMV. In addition, EBV protein EBNA-LP, which targets Sp100, also augments ICP0-null mutant HSV-1 replication. The combination of these two EBV regulatory proteins had a greater effect than each one individually. These findings reinforce the concept that disruption of the functions of PML-NB proteins is important for efficient herpesvirus infections. IMPORTANCE Whether a herpesvirus initiates a lytic infection in a host cell or establishes quiescence or latency is influenced by events that occur soon after the viral genome has entered the host cell nucleus. Certain cellular proteins respond in a restrictive manner to the invading pathogen's DNA, while viral functions are expressed that counteract the cell-mediated repression. One aspect of cellular restriction of herpesvirus infections is mediated by components of nuclear structures known as PML nuclear bodies (PML NBs), or ND10. Members of the alpha-, beta-, and gammaherpesvirus families all express proteins that interact with, degrade, or otherwise counteract the inhibitory effects of various PML NB components. Previous work has shown that there is the potential for a functional interchange between the viral proteins expressed by alpha- and betaherpesviruses, despite a lack of obvious sequence similarity. Here, this concept is extended to include a member of the gammaherpesviruses.

scholarly journals Antiherpesvirus Activities of Two Novel 4′-Thiothymidine Derivatives, KAY-2-41 and KAH-39-149, Are Dependent on Viral and Cellular Thymidine Kinases

2014 ◽  
Vol 58 (8) ◽  
pp. 4328-4340 ◽  
Author(s):  
Natacha Coen ◽  
Sophie Duraffour ◽  
Kazuhiro Haraguchi ◽  
Jan Balzarini ◽  
Joost J. van den Oord ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Antiviral Activity ◽  
Epstein Barr Virus ◽  
Varicella Zoster ◽  
Barr Virus ◽  
Epstein Barr ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACTThe emergence of drug-resistant herpesviruses represents a significant problem in clinical practice, primarily in immunocompromised patients. Furthermore, effective antiviral therapies against gammaherpesvirus-associated diseases are lacking. Here, we present two thiothymidine derivatives, KAY-2-41 and KAH-39-149, with different spectra of antiviral activity from those of the reference antiherpetic drugs, showing inhibitory activities against herpes simplex virus, varicella-zoster virus (VZV), and particularly against Epstein-Barr virus, with high selectivityin vitro. While KAY-2-41- and KAH-39-149-resistant herpesviruses were found to harbor mutations in the viral thymidine kinase (TK), these mutations conferred only low levels of resistance to these drugs but high levels to other TK-dependent drugs. Also, antiviral assays in HeLa TK-deficient cells showed a lack of KAY-2-41 and KAH-39-149 activities against herpes simplex virus 1 (HSV-1) and HSV-2 TK-deficient mutants. Furthermore, enzymatic TK assays showed the ability of HSV-1 TK, VZV TK, and cellular TK1 and TK2 to recognize and phosphorylate KAY-2-41 and KAH-39-149. These results demonstrate that the compounds depend on both viral and host TKs to exert antiviral activity. Additionally, the antiviral efficacy of KAH-39-149 proved to be superior to that of KAY-2-41 in a mouse model of gammaherpesvirus infection, highlighting the potential of this class of antiviral agents for further development as selective therapeutics against Epstein-Barr virus.

scholarly journals The Epstein-Barr Virus SM Protein Is Functionally Similar to ICP27 from Herpes Simplex Virus in Viral Infections

2002 ◽  
Vol 76 (18) ◽  
pp. 9420-9433 ◽  
Author(s):  
Julie L. Boyer ◽  
Sankar Swaminathan ◽  
Saul J. Silverstein
Keyword(s):  
Gene Expression ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Epstein Barr Virus ◽  
Common Mechanism ◽  
Barr Virus ◽  
Epstein Barr ◽  
Simplex Virus ◽  
Sm Protein ◽  
Hsv 1

ABSTRACT The herpes simplex virus type 1 (HSV-1) ICP27 protein is an essential RNA-binding protein that shuttles between the nucleus and cytoplasm to increase the cytoplasmic accumulation of viral late mRNAs. ICP27 homologs have been identified in each of the herpesvirus subfamilies, and accumulating evidence indicates that homologs from the gammaherpesvirus subfamily function similarly to ICP27. In particular, the Epstein-Barr virus (EBV) SM protein posttranscriptionally regulates gene expression, binds RNA in vitro and in vivo, and shuttles between the nucleus and cytoplasm. To determine if these two proteins function through a common mechanism, the ability of EBV SM to complement the growth defect of an HSV-1 ICP27-null virus was examined in a transient-expression assay. ICP27 stimulated the growth of the null mutant more efficiently than did SM, but the ability of SM to compensate for the ICP27 defects suggests conservation of common functions. To assay for complementation in the context of a viral infection, the growth properties of an HSV recombinant expressing SM in an ICP27-null background were analyzed. SM stimulated growth of the recombinant, although this growth was reduced by comparison to that of an ICP27-expressing virus. By contrast, an HSV recombinant expressing an SM mutant allele defective for transactivation activity and nucleocytoplasmic shuttling did not grow at all. These results suggest that SM and ICP27 may regulate gene expression through a common pathway that is evolutionarily conserved in herpesviruses.

scholarly journals Characterization and Intracellular Trafficking of Epstein-Barr Virus BBLF1, a Protein Involved in Virion Maturation

2012 ◽  
Vol 86 (18) ◽  
pp. 9647-9655 ◽  
Author(s):  
Ya-Fang Chiu ◽  
Bill Sugden ◽  
Pey-Jium Chang ◽  
Lee-Wen Chen ◽  
Ying-Ju Lin ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Retrograde Transport ◽  
Lytic Replication ◽  
Herpes Simplex Virus 1 ◽  
Virus Particles ◽  
Tegument Proteins ◽  
Barr Virus ◽  
Viral Maturation ◽  
Epstein Barr ◽  
Simplex Virus

Epstein-Barr virus (EBV) BBLF1 shares 13 to 15% amino acid sequence identities with the herpes simplex virus 1 UL11 and cytomegalovirus UL99 tegument proteins, which are involved in the final envelopment during viral maturation. This study demonstrates that BBLF1 is a myristoylated and palmitoylated protein, as are UL11 and UL99. Myristoylation of BBLF1 both facilitates its membrane anchoring and stabilizes it. BBLF1 is shown to localize to thetrans-Golgi network (TGN) along with gp350/220, a site where final envelopment of EBV particles takes place. The localization of BBLF1 at the TGN requires myristoylation and two acidic clusters, which interact with PACS-1, a cytosolic protein, to mediate retrograde transport from the endosomes to the TGN. Knockdown of the expression of BBLF1 during EBV lytic replication reduces the production of virus particles, demonstrating the requirement of BBLF1 to achieve optimal production of virus particles. BBLF1 is hypothesized to facilitate the budding of tegumented capsid into glycoprotein-embedded membrane during viral maturation.

scholarly journals The Epstein-Barr Virus Thymidine Kinase Does Not Phosphorylate Ganciclovir or Acyclovir and Demonstrates a Narrow Substrate Specificity Compared to the Herpes Simplex Virus Type 1 Thymidine Kinase

1998 ◽  
Vol 42 (11) ◽  
pp. 2923-2931 ◽  
Author(s):  
Erik A. Gustafson ◽  
Antoinette C. Chillemi ◽  
David R. Sage ◽  
Joyce D. Fingeroth
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Substrate Specificity ◽  
Thymidine Kinase ◽  
Epstein Barr Virus ◽  
Barr Virus ◽  
Epstein Barr ◽  
Simplex Virus ◽  
Hsv 1

ABSTRACT The Epstein-Barr virus (EBV) thymidine kinase (TK) was expressed in mammalian 143B TK− cells to investigate its substrate specificity. The herpes simplex virus type 1 (HSV-1) TK was similarly expressed for comparison. Both viral TKs conferred a TK+ phenotype on 143B TK− cells. The nucleoside analog ganciclovir (GCV) did not affect the growth of 143B EBV TK or 143B TK− cells but effectively killed 143B HSV-1 TK cells. Furthermore, lysates of 143B EBV TK cells could not phosphorylate GCV, which was confirmed by high-performance liquid chromatography. EBV TK, HSV-1 TK, and EBV TK N−, a truncated EBV TK missing 243 N-terminal amino acids, were purified as fusion proteins expressed in bacteria, and all had TK activity. In addition, EBV TK was observed to have a thymidylate kinase activity but could not phosphorylate GCV, acyclovir, or 2′-deoxycytidine. In competition assays, only nucleoside analogs of thymidine significantly inhibited thymidine phosphorylation by EBV TK, with the following rank order: 5-bromodeoxyuridine > zidovudine > stavudine > sorivudine. These results demonstrate that EBV TK substrate specificity is narrower than those of alphaherpesvirus TKs and that thymidine analogs may be the most suitable nucleoside antivirals to target the enzyme. Clinical implications for gammaherpesviruses are discussed.

scholarly journals Enterovirus and herpesviridae family as etiologic agents of lymphomonocytary meningitis, Southern Brazil

2011 ◽  
Vol 69 (3) ◽  
pp. 475-481 ◽  
Author(s):  
Luine Rosele Renaud Vidal ◽  
Sérgio Monteiro de Almeida ◽  
Iara José de Messias-Reason ◽  
Meri Bordignon Nogueira ◽  
Maria do Carmo Debur ◽  
...  
Keyword(s):  
Epstein Barr Virus ◽  
Herpes Virus ◽  
Viral Meningitis ◽  
Etiologic Agent ◽  
Herpes Simplex Virus 1 ◽  
Virus Family ◽  
Barr Virus ◽  
Epstein Barr ◽  
Herpès Virus ◽  
Simplex Virus

Viral meningitis is a common infectious disease of the central nervous system (CNS) that occurs worldwide. The aim of this study was to identify the etiologic agent of lymphomonocytary meningitis in Curitiba, PR, Brazil. During the period of July 2005 to December 2006, 460 cerebrospinal fluid (CSF) samples with lymphomonocytary meningitis were analyzed by PCR methodologies. Fifty nine (12.8%) samples were positive. Enteroviruses was present in 49 (83%) samples and herpes virus family in 10 (17%), of these 6 (10%) herpes simplex virus, 1 (2%) Epstein Barr virus, 2 (3%) human herpes virus type 6 and 1 (2%) mixed infection of enterovirus and Epstein Barr virus. As conclusion enterovirus was the most frequent virus, with circulation during summer and was observed with higher frequency between 4 to 17 years of age. PCR methodology is an important method for rapid detection of RNA enterovirus and DNA herpesvirus in CSF.

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