scholarly journals Selection of the same mutation in the U69 protein kinase gene of human herpesvirus-6 after prolonged exposure to ganciclovir in vitro and in vivo

2001 ◽  
Vol 82 (11) ◽  
pp. 2767-2776 ◽  
Author(s):  
Chaysavanh Manichanh ◽  
Camille Olivier-Aubron ◽  
Jean-Pierre Lagarde ◽  
Jean-Thierry Aubin ◽  
Phillipe Bossi ◽  
...  
Keyword(s):  
Amino Acid ◽  
Protein Kinase ◽  
Amino Acid Substitution ◽  
Consensus Sequence ◽  
Human Herpesvirus ◽  
Wild Type ◽  
Human Herpesvirus 6 ◽  
Genotypic Analysis ◽  
Herpesvirus 6

After serial passage in the presence of increasing concentrations of ganciclovir (GCV) in vitro, a human herpesvirus-6 (HHV-6) mutant exhibiting a decreased sensitivity to the drug was isolated. Analysis of drug susceptibility showed that the IC50 of this mutant was 24-, 52- and 3-fold higher than that of the wild-type (wt) IC50 in the case of GCV, cidofovir and foscarnet, respectively. Genotypic analysis showed two single nucleotide changes as compared to the wild-type: an A→G substitution of the U69 protein kinase (PK) gene resulted in an M318V amino acid substitution and the other change, located in the C-terminal part of the U38 gene, resulted in an A961V amino acid substitution within the DNA polymerase. The M318V change was located within the consensus sequence DISPMN of the putative catalytic domain VI of the PK. This change was homologous to the M460V and M460I changes that had been reported previously within the consensus sequence DITPMN of the human cytomegalovirus (HCMV) UL97 PK and associated with the resistance of HCMV to GCV. The M318V change was also detected by PCR in HHV-6-infected PBMCs from an AIDS patient who had been treated with GCV for a long period of time and exhibited a clinically GCV-resistant HCMV infection. These findings provide strong circumstantial evidence that the M318V change of the PK gene is associated with resistance to GCV and raise the question of cross resistance to this drug among different betaherpesviruses.

scholarly journals In vitro cellular tropism of human B-lymphotropic virus (human herpesvirus-6).

1988 ◽  
Vol 167 (5) ◽  
pp. 1659-1670 ◽  
Author(s):  
P Lusso ◽  
P D Markham ◽  
E Tschachler ◽  
F di Marzo Veronese ◽  
S Z Salahuddin ◽  
...  
Keyword(s):  
T Cell ◽  
T Lymphocytes ◽  
Cell Population ◽  
Mononuclear Cells ◽  
Human Herpesvirus ◽  
Human Herpesvirus 6 ◽  
Infected Cells ◽  
Cellular Tropism ◽  
Herpesvirus 6

We investigated the cellular tropism of human B-lymphotropic virus (HBLV) (also designated Human Herpesvirus-6) in vitro by infecting fresh MN cells from normal human adult peripheral blood, umbilical cord blood, bone marrow, tonsil, and thymus. Cultures from all the sources examined contained infectable cells, as shown by the appearance of characteristic enlarged, round-shaped, short-lived cells expressing HBLV-specific markers. Detailed immunological analysis demonstrated that the vast majority of these cells expressed T cell-associated antigens (i.e., CD7, CD5, CD2, CD4, and to a lesser extent, CD8). The CD3 antigen and the TCR-alpha/beta heterodimer were not detectable on the surface membrane, but were identified within the cytoplasm of HBLV-infected cells, by both immunofluorescence and radioimmunoprecipitation assay. A proportion of the HBLV-infected cell population also expressed the CD15 and class II MHC DR antigens. By means of immunoselection procedures it was possible to show that a consistent proportion of HBLV-infectable cells were contained within the CD3-depleted immature T cell population, while the depletion of CD2+ cells completely abrogated the infectability of the cultures. Northern blot analysis confirmed the T cell origin of HBLV-infected cells, demonstrating the expression of full size TCR-alpha and -beta chain mRNA. In addition to fresh T cells, HBLV was able to infect normal T lymphocytes expanded in vitro with IL-2 for greater than 30 d. These results indicate that HBLV is selectively T cell tropic in the course of the in vitro infection of normal mononuclear cells and may therefore be directly involved in the pathogenesis of T cell related hematological disorders. In particular, in light of the cytopathic effect exerted in vitro on CD4+ T lymphocytes, a possible role of HBLV in immune deficiency conditions should be considered.

In vitro sensitivity of human herpesvirus-6 to antiviral drugs

1989 ◽  
Vol 140 ◽  
pp. 219-228 ◽  
Author(s):  
H. Agut ◽  
H. Collandre ◽  
J.-T. Aubin ◽  
D. Guétard ◽  
V. Favier ◽  
...  
Keyword(s):  
Human Herpesvirus ◽  
Antiviral Drugs ◽  
Human Herpesvirus 6 ◽  
In Vitro Sensitivity ◽  
Herpesvirus 6

Maribavir Inhibits the Replication of Human Herpesvirus 6 and the Activity of the U69 Protein Kinase

2008 ◽  
Vol 78 (2) ◽  
pp. A29 ◽  
Author(s):  
Mark Prichard ◽  
Shannon Daily ◽  
Amie Perry ◽  
Earl Kern
Keyword(s):  
Protein Kinase ◽  
Human Herpesvirus ◽  
Human Herpesvirus 6 ◽  
Herpesvirus 6

Susceptibility of Human Herpesvirus 6 to Antivirals In Vitro

1990 ◽  
Vol 162 (3) ◽  
pp. 634-637 ◽  
Author(s):  
William H. Burns ◽  
Gordon R. Sandford
Keyword(s):  
Human Herpesvirus ◽  
Human Herpesvirus 6 ◽  
Herpesvirus 6

Inhibition of Cord Blood Cell Expansion by Human Herpesvirus 6 In Vitro

2004 ◽  
Vol 13 (2) ◽  
pp. 197-203 ◽  
Author(s):  
Andreas Nitsche ◽  
Jessika Fleischmann ◽  
Kai-Michael Klima ◽  
Aleksandar Radonić ◽  
Stefanie Thulke ◽  
...  
Keyword(s):  
Blood Cell ◽  
Cord Blood ◽  
Cell Expansion ◽  
Human Herpesvirus ◽  
Human Herpesvirus 6 ◽  
Cord Blood Cell ◽  
Herpesvirus 6

scholarly journals Functional Interaction between Human Herpesvirus 6 Immediate-Early 2 Protein and Ubiquitin-Conjugating Enzyme 9 in the Absence of Sumoylation

2006 ◽  
Vol 80 (20) ◽  
pp. 10218-10228 ◽  
Author(s):  
Andru Tomoiu ◽  
Annie Gravel ◽  
Robert M. Tanguay ◽  
Louis Flamand
Keyword(s):  
Human Herpesvirus ◽  
Immediate Early ◽  
Human Herpesvirus 6 ◽  
Interacting Protein ◽  
Ubiquitin Conjugating Enzyme ◽  
Herpesvirus 6 ◽  
Transcriptional Complex ◽  
Conjugating Enzyme

ABSTRACT The immediate-early 2 (IE2) protein of human herpesvirus 6 is a potent transactivator of cellular and viral promoters. To better understand the biology of IE2, we generated a LexA-IE2 fusion protein and screened, using the yeast two-hybrid system, a Jurkat T-cell cDNA library for proteins that could interact with IE2. The most frequently isolated IE2-interacting protein was the human ubiquitin-conjugating enzyme 9 (Ubc9), a protein involved in the small ubiquitin-like modifier (SUMO) conjugation pathway. Using deletion mutants of IE2, we mapped the IE2-Ubc9-interacting region to residues 989 to 1037 of IE2. The interaction was found to be of functional significance to IE2, as Ubc9 overexpression significantly repressed promoter activation by IE2. The C93S Ubc9 mutant exhibited a similar effect on IE2, indicating that the E2 SUMO-conjugating function of Ubc9 is not required for its repressive action on IE2. No consensus sumoylation sites or evidence of IE2 conjugation to SUMO could be demonstrated under in vivo or in vitro conditions. Moreover, expression levels and nuclear localization of IE2 were not altered by Ubc9 overexpression, suggesting that Ubc9's repressive function likely occurs at the transcriptional complex level. Overall, our results indicate that Ubc9 influences IE2's function and provide new information on the complex interactions that occur between herpesviruses and the sumoylation pathway.

scholarly journals Human Herpesvirus 6 Open Reading Frame U12 Encodes a Functional β-Chemokine Receptor

1998 ◽  
Vol 72 (7) ◽  
pp. 6104-6112 ◽  
Author(s):  
Yuji Isegawa ◽  
Zou Ping ◽  
Kazushi Nakano ◽  
Nakaba Sugimoto ◽  
Koichi Yamanishi
Keyword(s):  
Chemokine Receptors ◽  
Human Herpesvirus ◽  
Murine Cytomegalovirus ◽  
Human Herpesvirus 6 ◽  
Monocyte Chemoattractant Protein 1 ◽  
Reading Frame ◽  
Homologous Genes ◽  
Inflammatory Proteins ◽  
Herpesvirus 6

ABSTRACT Human herpesvirus 6 (HHV- 6), which belongs to the betaherpesvirus subfamily and infects mainly T cells in vitro, causes acute and latent infections. HHV- 6 contains two genes (U12 and U51) that encode putative homologs of cellular G-protein-coupled receptors (GCR), while three other betaherpesviruses, human cytomegalovirus, murine cytomegalovirus, and human herpesvirus 7, have three, one, and two GCR-homologous genes, respectively. The U12 gene is expressed late in infection from a spliced mRNA. The U12 gene was cloned, and the protein was expressed in cells and analyzed for its biological characteristics. U12 functionally encoded a calcium-mobilizing receptor for β-chemokines such as regulated upon activation, normal T expressed and secreted (RANTES), macrophage inflammatory proteins 1α and 1β (MIP-1α and MIP-1β) and monocyte chemoattractant protein 1 but not for the α-chemokine interleukin-8, suggesting that the chemokine selectivity of the U12 product was distinct from that of the known mammalian chemokine receptors. These findings suggested that the product of U12 may play an important role in the pathogenesis of HHV- 6 through transmembrane signaling by binding with β-chemokines.

scholarly journals Replication kinetics of a CHIKV Asian strain with 76 aa duplication in the nsP3 HVD, in comparison to the wild-type Asian and ECSA strains

2020 ◽  
Vol 2 (7A) ◽  
Author(s):  
Nurshariza Abdullah ◽  
Hong Wai Tham ◽  
Nafees Abdullah ◽  
Vinod RMT Balasubramaniam ◽  
I-Ching Sam ◽  
...  
Keyword(s):  
Amino Acid ◽  
Preliminary Finding ◽  
Wild Type ◽  
Replication Rate ◽  
Asian Strain ◽  
Genotypic Analysis ◽  
The Indian Ocean ◽  
Kinetics Of ◽  
Type Strains

Introduction: Chikungunya virus (CHIKV) is a mosquito-borne alphavirus which causes fever, rash and polyarthralgia. CHIKV has expanded its circulating regions to the Indian Ocean islands, Europe, Americas and Southeast Asia. Two CHIKV lineages, the ASIAN and ECSA are circulating in Malaysia. In 2009, a CHIKV strain with a 76 amino acid (aa) duplication in its nsP3 hypervariable domain (HVD), identified as CHIKvASIAN09MUM-Dup+ was isolated from a patient co-infected with DENV-2. Indels and duplication have been found in many other alphaviruses, and suggested to play a role in the survivality of the viruses. Objectives: We aim to compare and relate the replication kinetics and virulency in-vitro of CHIKvASIAN09MUM-Dup+ with the wild-type Asian and ECSA strains. Methods & Results: Genotypic analysis was conducted on three CHIKV strains in Malaysia, the CHIKvASIAN06UM-Dup-, CHIKvECSA08UM-Dup- and CHIKvASIAN09MUM-Dup+. We found that CHIKvASIAN09MUM-Dup+ has significant low replication rates in Vero, C6/36 and Rhabdosarcoma cells as compared to the wild-type strains. The highest titers were reached by CHIKvASIAN09MUM-Dup+ in all cells are 6.5 to 6.75 log10 TCID50/mL, which is 100 fold lower compared to the wild-type strains. Conclusion: The significantly low replication rate of Dup+ strain in all the cells, maybe suggestive to be due to co-infection and co-existence with DENV, where the aa duplication may play a role in overcoming competitive suppression. This preliminary finding agrees with reported events, where alphaviruses use insertion, deletion and duplication of amino acid in nsP3 HVD as strategies to influence replication in host, viral virulency, pathogenesis and survivality for evolution adaptation.

scholarly journals Impact of Human Cytomegalovirus and Human Herpesvirus 6 Infection on the Expression of Factors Associated with Cell Fibrosis and Apoptosis: Clues for Implication in Systemic Sclerosis Development

2020 ◽  
Vol 21 (17) ◽  
pp. 6397
Author(s):  
Maria-Cristina Arcangeletti ◽  
Maria D’Accolti ◽  
Clara Maccari ◽  
Irene Soffritti ◽  
Flora De Conto ◽  
...  
Keyword(s):  
Systemic Sclerosis ◽  
Human Cytomegalovirus ◽  
Human Herpesvirus ◽  
Dermal Fibroblasts ◽  
Target Cells ◽  
Human Herpesvirus 6 ◽  
Factors Associated ◽  
Herpesvirus 6

Systemic sclerosis (SSc) is a severe autoimmune disorder characterized by vasculopathy and multi-organ fibrosis; its etiology and pathogenesis are still largely unknown. Herpesvirus infections, particularly by human cytomegalovirus (HCMV) and human herpesvirus 6 (HHV-6), have been suggested among triggers of the disease based on virological and immunological observations. However, the direct impact of HCMV and/or HHV-6 infection on cell fibrosis and apoptosis at the cell microenvironment level has not yet been clarified. Thus, this study aimed to investigate the effects of HCMV and HHV-6 infection on the induction of pro-fibrosis or pro-apoptosis conditions in primary human dermal fibroblasts, one of the relevant SSc target cells. The analysis, performed by microarray in in vitro HCMV- or HHV-6-infected vs. uninfected cells, using specific panels for the detection of the main cellular factors associated with fibrosis or apoptosis, showed that both viruses significantly modified the expression of at least 30 pro-fibrotic and 20 pro-apoptotic factors. Notably, several recognized pro-fibrotic factors were highly induced, and most of them were reported to be involved in vivo in the multifactorial and multistep pathogenic process of SSc, thus suggesting a potential role of both HCMV and HHV-6.

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