The R3 Region, One of Three Major Repetitive Regions of Human Herpesvirus 6, Is a Strong Enhancer of Immediate-Early Gene U95

Takemoto, Masaya; Shimamoto, Takuya; Isegawa, Yuji; Yamanishi, Koichi

doi:10.1128/jvi.75.21.10149-10160.2001

Cited by 41 publications

(40 citation statements)

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“…The seven genes that were expressed independently of de novo protein synthesis (U81, U86, U94, U95, B3, B6, and B7) belonged to the classes I and II, showing the most rapid onset of expression consistent with these genes being IE genes. For three of these genes (U81, U94, and U95), our analysis confirmed their previous classification as IE genes (18,26,36). Furthermore, U86 is homologous to IE-A in HHV-6A (13) and IE2 (UL122) in HCMV, and therefore it is expected to be an IE gene.…”

Section: Discussionsupporting

confidence: 74%

Viral Gene Expression Patterns in Human Herpesvirus 6B-Infected T Cells

Øster

Höllsberg

2002

J Virol

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Herpesvirus gene expression is divided into immediate-early (IE) or ␣ genes, early (E) or ␤ genes, and late (L) or ␥ genes on the basis of temporal expression and dependency on other gene products. By using real-time PCR, we have investigated the expression of 35 human herpesvirus 6B (HHV-6B) genes in T cells infected by strain PL-1. Kinetic analysis and dependency on de novo protein synthesis and viral DNA polymerase activity suggest that the HHV-6B genes segregate into six separate kinetic groups. The genes expressed early (groups I and II) and late (groups V and VI) corresponded well with IE and L genes, whereas the intermediate groups III and IV contained E and L genes. Although HHV-6B has characteristics similar to those of other roseoloviruses in its overall gene regulation, we detected three B-variant-specific IE genes. Moreover, genes that were independent of de novo protein synthesis clustered in an area of the viral genome that has the lowest identity to the HHV-6A variant. The organization of IE genes in an area of the genome that differs from that of HHV-6A underscores the distinct differences between HHV-6B and HHV-6A and may provide a basis for further molecular and immunological analyses to elucidate their different biological behaviors.In the mid-and late 1980s human herpesvirus 6A (HHV-6A) and HHV-6B were discovered and subsequently named as variants of 20,32,34). Although they share approximately 90% nucleotide sequence identity (13, 18), the accumulating biological, genetic, and epidemiological data suggest that these viruses have independent biological functions (13,18,34,37,38). Whereas little is known about the disease potential of HHV-6A, HHV-6B is the causative agent of the childhood disease exanthem subitum, characterized by a few days of high fever followed by a rash appearing with fever subsidence (34, 39). Thus, the frequency of HHV-6B seropositive individuals reaches almost 100% in early childhood (7, 10), but late primary infection may provoke a mononucleosislike disease similar to human cytomegalovirus (HCMV) mononucleosis. In addition, HHV-6B is thought to be involved in a number of other conditions, including encephalitis and neoplasia (2, 3).HHV-6B displays primarily tropism for T cells and monocytes (22,24). The virus enters the cells in part via binding to the ubiquitously expressed glycoprotein CD46 (33), but additional cellular proteins involved in virus entry still remain to be discovered (6, 33). As with other herpesviruses, HHV-6 establishes latency following the primary infection. In addition to its tropism for mononuclear cells, HHV-6 is highly neurotropic and may also reside in astrocytes within the central nervous system (8, 15), and it remains to be determined which cells harbor the majority of the latent virus (21, 23). Of clinical significance, HHV-6 is an important pathogen when reactivated in immunocompromised hosts, such as patients with AIDS, leukemia, lymphoma, and solid organ or bone marrow transplants (3).The entire genomes of HHV-6B strains Z29 and HST have...

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Section: Discussionsupporting

confidence: 74%

Viral Gene Expression Patterns in Human Herpesvirus 6B-Infected T Cells

Øster

Höllsberg

2002

J Virol

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“…The comparison of kinetic classifications of HHV-6 genes between different studies showed that, despite the use of different methodologies, viral variants and strains, the consistent classification of U90 and U95 as IE genes (Isegawa et al, 1998;Schiewe et al, 1994;Takemoto et al, 2001), of U41, U51 and U69 as E genes Mirandola et al, 1998) and of U22 and U100 as L genes [no detectable transcription in the presence of PAA as reported by French et al (1999) and Mirandola et al (1998)] suggests that these represent ideal markers for determining the stages of HHV-6 lytic replication.…”

Section: Discussionmentioning

confidence: 99%

Microarray-based determination of the lytic cascade of human herpesvirus 6B

Tsao

Kellam

Sin

et al. 2009

Journal of General Virology

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The lytic gene expression of several members of the human herpesvirus family has been profiled by using gene-expression microarrays; however, the lytic cascade of roseoloviruses has not been studied in similar depth. Based on the complete DNA genome sequences of human herpesvirus 6 variant A (HHV-6A) and variant B (HHV-6B), we constructed a cDNA microarray containing DNA probes to their predicted open reading frames, plus 914 human genes. Gene-expression profiling of HHV-6B strain Z29 in SupT1 cells over a 60 h time-course post-infection, together with kinetic classification of the HHV-6B genes in the presence of either cycloheximide or phosphonoacetic acid, allowed the placement of HHV-6B genes into defined kinetic classes. Eighty-nine HHV-6B genes were divided into four different expression kinetic classes: eight immediate-early, 44 early, 33 late and four biphasic. Clustering of genes with similar expression profiles implied a shared function, thus revealing possible roles of previously uncharacterized HHV-6B genes. INTRODUCTIONHuman herpesvirus 6 (HHV-6) is a betaherpesvirus, first isolated in 1986 from individuals with lymphoproliferative disorders (Salahuddin et al., 1986). Primary infection occurs in early childhood (Hall et al., 1994), when it can cause febrile illnesses including exanthem subitum (ES) (Yamanishi et al., 1988;Zerr et al., 2005). Following initial infection, HHV-6 establishes lifelong latency in the host, with monocytes (Kondo et al., 1991) and bone-marrow progenitor cells (Luppi et al., 1999) being suggested as the sites of latency. HHV-6 reactivation in immunocompromised hosts can be pathogenic, particularly in the transplant setting, and has been associated with encephalitis, bone-marrow suppression and graft rejection (Clark & Griffiths, 2003).Two variants of HHV-6 exist (-6A and -6B), each with distinct genetic, antigenic and biological properties (Pellett & Black, 1996; Schirmer et al., 1991). HHV-6A is not associated consistently with disease, but HHV-6B is the cause of ES in childhood (Dewhurst et al., 1993;Yamanishi et al., 1988;Zerr et al., 2005). Publication of the complete DNA genome sequences of HHV-6A and -6B (Dominguez et al., 1999;Gompels et al., 1995;Isegawa et al., 1999) confirmed the close relatedness of the two variants.However, significant sequence variations observed at the right end of the unique region, plus the existence of variant-specific open reading frames (ORFs), may explain the differential properties described for HHV-6A and -6B (Clark, 2000).As HHV-6 replicates predominantly in CD4 + T cells in vitro and in vivo (Lopez et al., 1988;Lusso et al., 1988), there is interest in the regulation of viral gene expression in its target cell type. We have previously described the use of DNA microarrays for expression profiling of two gammaherpesviruses, Kaposi's sarcoma-associated herpesvirus (Jenner et al., 2001) and murine gammaherpesvirus 68 (Ahn et al., 2002), and demonstrated the functional predictions of uncharacterized viral genes and transcription from inte...

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“…Umbilical cord blood mononuclear cells (CBMCs) were separated on a Ficoll-Conray gradient and cultured in RPMI medium containing 10% fetal bovine serum, phytohemagglutinin (5 g/ml), and interleukin-2 (IL-2) (2 ng/ml) (29). HHV-6A strain U1102 or HHV-6B strain HST was propagated in stimulated CBMCs (1).…”

Section: Cells and Viruses The Human T-lymphoblastoid Cell Lines Jjhmentioning

confidence: 99%

Complementation of the Function of Glycoprotein H of Human Herpesvirus 6 Variant A by Glycoprotein H of Variant B in the Virus Life Cycle

Oyaizu

Tang

Ota

et al. 2012

J Virol

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dHuman herpesvirus 6 (HHV-6) is a T-cell-tropic betaherpesvirus. HHV-6 can be classified into two variants, HHV-6 variant A (HHV-6A) and HHV-6B, based on genetic, antigenic, and cell tropisms, although the homology of their entire genomic sequences is nearly 90%. The HHV-6A glycoprotein complex gH/gL/gQ1/gQ2 is a viral ligand that binds to the cellular receptor human CD46. Because gH has 94.3% amino acid identity between the variants, here we examined whether gH from one variant could complement its loss in the other. Recently, we successfully reconstituted HHV-6A from its cloned genome in a bacterial artificial chromosome (BAC) (rHHV-6ABAC). Using this system, we constructed HHV-6ABAC DNA containing the HHV-6B gH (BgH) gene instead of the HHV-6A gH (AgH) gene in Escherichia coli. Recombinant HHV-6ABAC expressing BgH (rHHV-6ABAC-BgH) was successfully reconstituted. In addition, a monoclonal antibody that blocks HHV-6B but not HHV-6A infection neutralized rHHV-6ABAC-BgH but not rHHV-6ABAC. These results indicate that HHV-6B gH can complement the function of HHV-6A gH in the viral infectious cycle.

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The R3 Region, One of Three Major Repetitive Regions of Human Herpesvirus 6, Is a Strong Enhancer of Immediate-Early Gene U95

Cited by 41 publications

References 55 publications

Viral Gene Expression Patterns in Human Herpesvirus 6B-Infected T Cells

Viral Gene Expression Patterns in Human Herpesvirus 6B-Infected T Cells

Microarray-based determination of the lytic cascade of human herpesvirus 6B

Complementation of the Function of Glycoprotein H of Human Herpesvirus 6 Variant A by Glycoprotein H of Variant B in the Virus Life Cycle

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