Identification of homologues to the human cytomegalovirus US22 gene family in human herpesvirus 6

Efstathiou, Stacey; Lawrence, Glenda; Brown, C. B.; Barrell, Bart

doi:10.1099/0022-1317-73-7-1661

Journal of General Virology

1992

DOI: 10.1099/0022-1317-73-7-1661

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Identification of homologues to the human cytomegalovirus US22 gene family in human herpesvirus 6

Stacey Efstathiou

Glenda Lawrence²,

C. B. Brown³

et al.

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Cited by 44 publications

(47 citation statements)

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“…This gene family is characterized by the presence of one, two, three, or four conserved motifs (4,7,8,12,24,25,27). Consensus sequences for motifs I and II have been identified, and they contain short stretches of hydrophobic and charged residues.…”

mentioning

confidence: 99%

Products of US22 Genes M140 and M141 Confer Efficient Replication of Murine Cytomegalovirus in Macrophages and Spleen

Hanson

Slater

Karabekian

et al. 2001

J Virol

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Efficient replication of murine cytomegalovirus (MCMV) in macrophages is a prerequisite for optimal growth and spread of the virus in its natural host. Simultaneous deletion of US22 gene family members M139, M140, and M141 results in impaired replication of MCMV in macrophages and mice. In this study, we characterized the proteins derived from these three genes and examined the impact of individual gene deletions on viral pathogenesis. The M139, M140, and M141 gene products were identified as early proteins that localize to both the nucleus and cytoplasm in infected cells. Gene M139 encodes two proteins, of 72 and 61 kDa, while M140 and M141 each encode a single protein of 56 (pM140) and 52 (pM141) kDa, respectively. No role for the M139 proteins in MCMV replication in macrophages or mice was determined in these studies. In contrast, deletion of either M140 or M141 resulted in impaired MCMV replication in macrophages and spleen tissue. Replication of the M140 deletion mutant was significantly more impaired than that of the virus lacking M141. Further analyses revealed that the absence of the pM140 adversely affected pM141 levels by rendering the latter protein unstable. Since the replication defect due to deletion of M140 was more profound than could be explained by the reduced half-life of pM141, pM140 must exert an additional, independent function in mediating efficient replication of MCMV in macrophages and spleen tissue. These data indicate that the US22 genes M140 and M141 function both cooperatively and independently to regulate MCMV replication in a cell type-specific manner and, thus, to influence viral pathogenesis.The US22 genes of cytomegalovirus (CMV) are members of a multigene family unique to the betaherpesviruses. This gene family is characterized by the presence of one, two, three, or four conserved motifs (4,7,8,12,24,25,27). Consensus sequences for motifs I and II have been identified, and they contain short stretches of hydrophobic and charged residues. The less-well-defined motifs III and IV also have stretches of nonpolar residues. At the left end of betaherpesvirus genomes is a cluster of US22 family genes that exhibit homology among human CMV (HCMV) genes (UL23, UL24, UL28, and UL29), murine CMV (MCMV) genes (M23, M24, m25.1, and m25.2), and human herpesvirus 6 (HHV-6) or HHV-7 genes (U2, U3, U7, and U8). Farther downstream are HCMV US22 genes UL36 and UL43, which are respectively homologous to M36 and M43 in MCMV and to U16/17 and U25 in HHV-6 or HHV-7. At the right end of the MCMV genome is US22 gene M128 (ie2), which is homologous to the HHV-6 or HHV-7 U95 gene. Finally, at the far right end of the HCMV and MCMV genomes lies another cluster of US22 genes not present in HHV-6 or HHV-7. They are HCMV genes US22, US23, US24, US26, and IRS1/TRS1 and homologous MCMV genes M139, M140, M141, m142, and m143.At least two US22 genes within each betaherpesvirus genome appear to function as transcriptional transactivators of heterologous promoters. These include HCMV immediateearly (IE) genes UL36 ...

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mentioning

confidence: 99%

Products of US22 Genes M140 and M141 Confer Efficient Replication of Murine Cytomegalovirus in Macrophages and Spleen

Hanson

Slater

Karabekian

et al. 2001

J Virol

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“…HHV-6 is classified as a member of the betaherpesviruses, represented by human cytomegalovirus (HCMV) as well as HHV-7. This classification was made on the basis of the evolutionary divergence of its genome sequence from other subgroups (6,14,15,19,22,29,37). The betaherpesviruses have extensive domains of similar genetic organization, the conserved herpesvirus gene blocks, in the unique region of their genome, and they include a number of gene families that are characteristic of this subgroup (10).…”

mentioning

confidence: 99%

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

Takemoto

Shimamoto

Isegawa

et al. 2001

J Virol

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An immediate-early (IE) gene of human herpesvirus 6 (HHV-6), U95, has similarity at the amino acid level to the murine cytomegalovirus (MCMV) IE2 gene and is related to the human cytomegalovirus (HCMV) US22 gene family. Sequence analyses of U95 cDNA clones revealed that the transcription start site was located about 1.6 kbp upstream of the putative initiating ATG and that the transcript consisted of two exons. A single intron extended from nucleotides 142589 to 144229, which contained ORF U94. A protein with a molecular mass of about 120 kDa was translated from this cDNA clone in an in vitro transcription-translation assay. The transcription start site was found to be 220 bp downstream of the R3 region by primer extension analysis. HHV-6 has three repetitive elements, R1, R2, and R3, in or near the IE-A locus. R3 is composed of 24 copies of a 104-to 107-bp sequence element, which contains multiple putative binding sites for cellular transcription factors such as AP2 and NF-B, and its biological significance has yet to be elucidated. The region between ؊710 and ؉46 relative to the transcription start site of U95 was analyzed in this study. Deletion from ؊710 to ؊396, corresponding to three copies of an R3 unit, decreased the promoter activity by 15-fold, and coexpression of IB␣(S32A/S36A) repressed it to almost the same level. Electrophoretic mobility shift assays showed that NF-B family members p50 and c-Rel bound to NF-B sites derived from the R3 region. These results demonstrate that R3 strongly enhances the U95 promoter activity and that NF-B and binding sites for NF-B in the R3 region play an important role in its activation. Because U95 promoter activity correlated with the number of R3 units, which each contained an NF-B site, the repetitive organization of R3 is important for regulating U95 transcription.

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“…Screening for open reading frames (ORFs) encoding > 100 amino acids with initiating methionine allowed us to identify two rightwards ORFs, SJRF 1 and SJRF2. SJRF2 overlapped by 36bp with the leftward ORF SHL1, previously described as a member of the HCMV US22 family of transcriptional activator genes (Efstathiou et al, 1992). The telomeric repeat region was open in two frames from either strand, the ORF encoding the RV repeated amino acids was depicted as the initiating methionine conforms to consensus (Kozak, 1984).…”

mentioning

confidence: 99%

“…Primer sets, with BamHI sites to facilitate cloning, were used to amplify DNA sequences from JJhan cells infected with the earliest passages of strain U 1102 available (P2) (Downing et al, 1987) to avoid effects of continuous culture. The HHV-6 SmaI J sequence at the DRL-U L junction was amplified (conditions described in Gompels et al, 1993) using two primers, 5' CATGAGAGGATCCTGGACG-TACTC 3' and 5' CGAGGATCCGGAGACGGAGG-AGTC 3', derived from sequence in the adjacent SmaIL and SalI H fragments (Lawrence, 1991 ;Efstathiou et al, 1992); the amplified sequence was then cloned into pUC18 and the resulting construct was designated pSMJ6. Sonicated fragments of insert DNA and the original amplification product were end-repaired with Klenow polymerase and ligated with SmaI-digested/ phosphatased M13mpl8 (Messing, 1983).…”

mentioning

confidence: 99%

Characterization of human telomeric repeat sequences from human herpesvirus 6 and relationship to replication

1995

Journal of General Virology

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Here we examine by polymerase chain reaction amplification followed by cloning and sequence analyses selected regions of the human herpesvirus 6 (HHV-6) genome which contain human telomeric repeats (TTA-GGG). We determine the relative number, arrangement and orientation of the repeats in the unit length genome, in concatemeric replicative intermediates and in heterogeneous (het) regions. We also examine distribution of the repeats in the entire genome (159 kb) and their orientation relative to DNA packaging motifs and the origin of lytic replication. In the prototype orientation the HHV-6 repeat is the related complement, TAACCC. We show that tandem arrays of this repeat are present in the right and left long direct repeats (DR L and DR R, 8 kb each) which bound the long unique sequence (U L, 143 kb). Within each DR there is a left terminal imperfect tandem array and a right terminal perfect tandem array (58 copies). In DR they are each adjacent to DNA packaging motifs, pacl and pac2, described for herpes simplex virus and human cytomegalovirus, in the arrangement pacl-imperfect repeat-7.2 kb-perfect repeat-pac2. Five independent clones were isolated and sequence determined from junctions of concatemeric replicative intermediates which showed adjacent pac2 and pacl motifs surrounded by telomeric repeats. Favoured cleavage sites for unit length genomes were indicated which avoided cleavage within the repeats. Analyses of the complete genome showed no tandem repeats within U L but did show a polar distribution of monomeric copies and related sequences around the origin of replication, with an effect on the overall base composition. The implications for virus replication are discussed.Human herpesvirus 6 (HHV-6) is one of the most recently characterized of the family of seven human herpesviruses. Like other herpesviruses it can establish a latent or persistent infection which remains for the lifetime of the host and can reactivate during immunosuppression. HHV-6 infects up to 90 % of the population as infants where infection is asymptomatic or causes exanthem subitum, a mild skin rash (Yamanishi et al., 1988;Okuno et al., 1989). The virus has a cellular tropism for CD4 + T lymphocytes and there is evidence for the monocyte as a possible site for latency. HHV-6 strains were first isolated from blood samples from AIDS patients where the virus had reactivated (Salahuddin et al., 1986;Downing et al., 1987). Given the similar cellular tropisms of human immunodeficiency virus

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Identification of homologues to the human cytomegalovirus US22 gene family in human herpesvirus 6

Cited by 44 publications

References 58 publications

Products of US22 Genes M140 and M141 Confer Efficient Replication of Murine Cytomegalovirus in Macrophages and Spleen

Products of US22 Genes M140 and M141 Confer Efficient Replication of Murine Cytomegalovirus in Macrophages and Spleen

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

Characterization of human telomeric repeat sequences from human herpesvirus 6 and relationship to replication

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