scholarly journals Human Herpesvirus 6 Open Reading Frame U83 Encodes a Functional Chemokine

1999 ◽  
Vol 73 (7) ◽  
pp. 5926-5933 ◽  
Author(s):  
Ping Zou ◽  
Yuji Isegawa ◽  
Kazusi Nakano ◽  
M. Haque ◽  
Yasuhiko Horiguchi ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Mononuclear Cells ◽  
Biological Function ◽  
Human Herpesvirus ◽  
Open Reading Frame ◽  
Pcr Analysis ◽  
Human Herpesvirus 6 ◽  
Antibody Testing ◽  
Reading Frame ◽  
Herpesvirus 6

ABSTRACT Some viruses including herpesviruses have undergone evolution to benefit viral infection and propagation by pirating and modifying host genes such as chemokine genes. Human herpesvirus 6 (HHV-6), acutely or persistently infects mononuclear cells in vitro. DNA sequence analysis of HHV-6 has revealed that the putative protein encoded by an open reading frame (ORF) of the U83 gene in HHV-6 variant B resembled a human chemokine. We have cloned the U83 gene and analyzed the biological function of this gene. The U83 gene contained an ORF encoding a 113-amino-acid peptide, starting at the first methionine and containing a possible signal peptide and the typical cysteine residues characteristic of the chemokines. Reverse transcription-PCR analysis of mRNA and immunofluorescent-antibody testing of infected cells both indicated that the encoded protein was a late protein. The ORF U83 gene fused to the Fc gene was expressed as a fusion protein in COS-7 cells by transfection, and the fusion protein was purified from the supernatant of transfected cells to test its biological function. The purified protein was capable of inducing transient calcium mobilization in THP-1 cells and of chemotactically activating THP-1 cells. These findings suggested that the U83 protein might play an important role in HHV-6 propagation in vivo by activating and trafficking mononuclear cells to sites of viral replication, thus aiding the development of superbly efficient virus production mechanisms.

Identification and characterization of the gene products of open reading frame U86/87 of human herpesvirus 6

2002 ◽  
Vol 89 (1) ◽  
pp. 89-101 ◽  
Author(s):  
Eleni Papanikolaou ◽  
Vlassis Kouvatsis ◽  
Georgios Dimitriadis ◽  
Naoki Inoue ◽  
Minas Arsenakis
Keyword(s):  
Human Herpesvirus ◽  
Open Reading Frame ◽  
Gene Products ◽  
Human Herpesvirus 6 ◽  
Reading Frame ◽  
Herpesvirus 6 ◽  
Identification And Characterization

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.

scholarly journals Human herpesvirus 6: infection and disease following autologous and allogeneic bone marrow transplantation

Blood ◽  
1996 ◽  
Vol 87 (12) ◽  
pp. 5341-5354 ◽  
Author(s):  
MP Kadakia ◽  
WB Rybka ◽  
JA Stewart ◽  
JL Patton ◽  
FR Stamey ◽  
...  
Keyword(s):  
Marrow Transplantation ◽  
Mononuclear Cells ◽  
Allogeneic Bone Marrow Transplantation ◽  
Human Herpesvirus ◽  
Clinical Event ◽  
Allogeneic Bone ◽  
Human Herpesvirus 6 ◽  
Peripheral Blood Mononuclear ◽  
Antibody Titers ◽  
Herpesvirus 6

Human herpesvirus 6 activity (HHV-6) was studied in 15 allogeneic and 11 autologous marrow transplantation patients. After transplantation, HHV-6 was isolated from the peripheral blood mononuclear cells of 12 of 26 patients (6 allogeneic and 6 autologous). All isolates were variant B. Eleven of 26 and 12 of 19 patients showed salivary shedding of HHV-6 DNA before and after transplantation, respectively. The antibody titer increased in 7 of 26 patients. Thus, 23 of 26 patients showed evidence of active HHV-6 infection either by virus isolation, salivary shedding, or increases in antibody titers. The fraction of saliva specimens positive in 19 patients was negatively associated with their antibody titers (P= .005). The proportion of cultures positive increased after transplantation (P = .007). Sinusitis was associated with HHV-6 isolation in autologous recipients (P= .002). In allogeneic patients, active human cytomegalovirus infection was associated with HHV-6 isolation (P = .04). No association was observed between HHV-6 infection and GVHD, pneumonia, delay in engraftment, or marrow suppression. Of the 120 clinical events analyzed in 26 patients, HHV-6 was defined as a probable cause of 16 events in 9 patients based on the propinquity of HHV-6 activity and the clinical event plus the absence of other identified causes of the event.

scholarly journals Characterization of the Human Herpesvirus 6 U69 Gene Product and Identification of Its Nuclear Localization Signal

2007 ◽  
Vol 82 (2) ◽  
pp. 710-718 ◽  
Author(s):  
Yuji Isegawa ◽  
Yoichi Miyamoto ◽  
Yoshinari Yasuda ◽  
Katsunori Semi ◽  
Kenji Tsujimura ◽  
...  
Keyword(s):  
Fusion Protein ◽  
Nuclear Localization ◽  
Nuclear Transport ◽  
Human Herpesvirus ◽  
Small Gtpase ◽  
Terminal Region ◽  
Mutant Form ◽  
Human Herpesvirus 6 ◽  
Importin Α ◽  
Herpesvirus 6

ABSTRACT To elucidate the function of the U69 protein kinase of human herpesvirus 6 (HHV-6) in vivo, we first analyzed its subcellular localization in HHV-6-infected Molt 3 cells by using polyclonal antibodies against the U69 protein. Immunofluorescence studies showed that the U69 signal localized to the nucleus in a mesh-like pattern in both HHV-6-infected and HHV6-transfected cells. A computer program predicted two overlapping classic nuclear localization signals (NLSs) in the N-terminal region of the protein; this NLS motif is highly conserved in the N-terminal region of most of the herpesvirus protein kinases examined to date. An N-terminal deletion mutant form of the protein failed to enter the nucleus, whereas a fusion protein of green fluorescent protein (GFP) and/or glutathione S-transferase (GST) and the U69 N-terminal region was transported into the nucleus, demonstrating that the predicted N-terminal NLSs of the protein actually function as NLSs. The nuclear transport of the GST-GFP fusion protein containing the N-terminal NLS of U69 was inhibited by wheat germ agglutinin and by the Q69L Ran-GTP mutant, indicating that the U69 protein is transported into the nucleus from the cytoplasm via classic nuclear transport machinery. A cell-free import assay showed that the nuclear transport of the U69 protein was mediated by importin α/β in conjunction with the small GTPase Ran. When the import assay was performed with a low concentration of each importin-α subtype, NPI2/importin-α7 elicited more efficient transport activity than did Rch1/importin-α1 or Qip1/importin-α3. These results suggest a relationship between the localization of NPI2/importin-α7 and the cell tropism of HHV-6.

Human Herpesvirus-6 (HHV-6) infection in multiple sclerosis: a preliminary report

1998 ◽  
Vol 4 (6) ◽  
pp. 490-496 ◽  
Author(s):  
D V Ablashi ◽  
W Lapps ◽  
M Kaplan ◽  
J E Whitman ◽  
J R Richert ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mononuclear Cells ◽  
Neurological Diseases ◽  
Human Herpesvirus ◽  
Human Herpesvirus 6 ◽  
Igg Antibody ◽  
Peripheral Blood Mononuclear ◽  
Barr Virus ◽  
Early Protein ◽  
Herpesvirus 6

We examined cerebra! spinal fluid (CSF) from multiple sclerosis (MS) patients and patients with other neurological diseases (OND) for antibody specific for Human Herpesvirus-6 (HHV-6) and for HHV-6 DNA detectable by PCR. CSF from MS patients had a higher frequency of IgG antibody to HHV-6 late antigens (39.4%) compared with CSF from OND (7.4%). In contrast, the frequency of detectable IgG antibody in CSF from MS patients specific for Epstein-Barr Virus (EBV) (12.1%) and Human Cytomegalovirus (HCMV) (6.1%) was much lower. Two of 12 MS CSFs (16.7%) also contained HHV-6 DNA detected by PCR. None of four OND CSF were positive for HHV-6 DNA. Plasma from 16 patients with MS, eight with OND and 72 healthy donors were tested for antibodies by ELISA to HHV-6 early (p41/38) and late (gp 110) proteins. Although no differences in ant-gp 110 IgG antibody were detected between MS patients, patients with other neurological diseases, and normals, IgG antibody to early protein p41/38 was detected in > 68% of the plasma from MS patients, 12.5% from OND patient and 27.8% of the controls. IgM antibody to p41/38 was present in >56% of MS patients, 12.5% of OND patients, and 19% of controls. These data suggest that more than half of the MS patients had active, ongoing HHV-6 infections. HHV-6 was also isolated from peripheral blood mononuclear cells (PBMC) from 3/5 MS patients who were in relapse or had progressive disease and was identified as HHV-6 Variant B. These preliminary results support the hypothesis that HHV-6 may be a co-factor in the pathogenesis of some cases of MS.

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 Human Herpesvirus 6 Infects Dendritic Cells and Suppresses Human Immunodeficiency Virus Type 1 Replication in Coinfected Cultures

1999 ◽  
Vol 73 (5) ◽  
pp. 4019-4028 ◽  
Author(s):  
Hideo Asada ◽  
Vera Klaus-Kovtun ◽  
Hana Golding ◽  
Stephen I. Katz ◽  
Andrew Blauvelt
Keyword(s):  
Human Immunodeficiency Virus ◽  
Dendritic Cells ◽  
Mononuclear Cells ◽  
Human Herpesvirus ◽  
Interleukin 4 ◽  
Human Herpesvirus 6 ◽  
Aids Patients ◽  
Peripheral Blood Mononuclear ◽  
Immunodeficiency Virus ◽  
Herpesvirus 6

ABSTRACT Human herpesvirus 6 (HHV-6) has been implicated as a cofactor in the progressive loss of CD4+ T cells observed in AIDS patients. Because dendritic cells (DC) play an important role in the immunopathogenesis of human immunodeficiency virus (HIV) disease, we studied the infection of DC by HHV-6 and coinfection of DC by HHV-6 and HIV. Purified immature DC (derived from adherent peripheral blood mononuclear cells in the presence of granulocyte-macrophage colony-stimulating factor and interleukin-4) could be infected with HHV-6, as determined by PCR analyses, intracellular monoclonal antibody staining, and presence of virus in culture supernatants. However, HHV-6-infected DC demonstrated neither cytopathic changes nor functional defects. Interestingly, HHV-6 markedly suppressed HIV replication and syncytium formation in coinfected DC cultures. This HHV-6-mediated anti-HIV effect was DC specific, occurred when HHV-6 was added either before or after HIV, and was not due to decreased surface expression or function of CD4, CXCR4, or CCR5. Conversely, HIV had no demonstrable effect on HHV-6 replication. These findings suggest that HHV-6 may protect DC from HIV-induced cytopathicity in AIDS patients. We also demonstrate that interactions between HIV and herpesviruses are complex and that the observable outcome of dual infection is dependent on the target cell type.

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