Functional Identification and Analysis of
            <i>cis</i>
            -Acting Sequences Which Mediate Genome Cleavage and Packaging in Human Herpesvirus 6

Deng, Hongyu; Dewhurst, Stephen

doi:10.1128/jvi.72.1.320-329.1998

Cited by 37 publications

(7 citation statements)

References 37 publications

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“…The mechanism for inserting these nucleotides is not obvious, although the variability is unlikely to be an artifact since it was observed in independently derived clones from different viral stocks and HHV-6A. Similar heterogeneity was also observed in clones derived from plasmid concatemers that had been packaged into extracellular virions or intracellular nucleocapsids (11).…”

Section: Fig 2 (A) Dr L and Dr R In Linear And Concatemeric Genomesmentioning

confidence: 73%

Human Herpesvirus 6B Genome Sequence: Coding Content and Comparison with Human Herpesvirus 6A

Dominguez

Dambaugh

Stamey

et al. 1999

J Virol

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311

164

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Human herpesvirus 6 variants A and B (HHV-6A and HHV-6B) are closely related viruses that can be readily distinguished by comparison of restriction endonuclease profiles and nucleotide sequences. The viruses are similar with respect to genomic and genetic organization, and their genomes cross-hybridize extensively, but they differ in biological and epidemiologic features. Differences include infectivity of T-cell lines, patterns of reactivity with monoclonal antibodies, and disease associations. Here we report the complete genome sequence of HHV-6B strain Z29 [HHV-6B(Z29)], describe its genetic content, and present an analysis of the relationships between HHV-6A and HHV-6B. As sequenced, the HHV-6B(Z29) genome is 162,114 bp long and is composed of a 144,528-bp unique segment (U) bracketed by 8,793-bp direct repeats (DR). The genomic sequence allows prediction of a total of 119 unique open reading frames (ORFs), 9 of which are present only in HHV-6B. Splicing is predicted in 11 genes, resulting in the 119 ORFs composing 97 unique genes. The overall nucleotide sequence identity between HHV-6A and HHV-6B is 90%. The most divergent regions are DR and the right end of U, spanning ORFs U86 to U100. These regions have 85 and 72% nucleotide sequence identity, respectively. The amino acid sequences of 13 of the 17 ORFs at the right end of U differ by more than 10%, with the notable exception of U94, the adeno-associated virus type 2 rep homolog, which differs by only 2.4%. This region also includes putative cis-acting sequences that are likely to be involved in transcriptional regulation of the major immediate-early locus. The catalog of variant-specific genetic differences resulting from our comparison of the genome sequences adds support to previous data indicating that HHV-6A and HHV-6B are distinct herpesvirus species.

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Section: Fig 2 (A) Dr L and Dr R In Linear And Concatemeric Genomesmentioning

confidence: 73%

Human Herpesvirus 6B Genome Sequence: Coding Content and Comparison with Human Herpesvirus 6A

Dominguez

Dambaugh

Stamey

et al. 1999

J Virol

Self Cite

311

164

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show abstract

“…Additional elements present in the end-terminal DR regions of HHV-7 and located adjacent to Pac-1 and Pac-2 include two large telomeric repeat regions (T1, T2). The T1 and T2 regions are composed of reiterations of the TAACCC telomeric motif ( 41 , 42 ). Homologous recombination between viral and chromosomal telomeric repeat sequences is thought to be the mechanism that allows viral integration into subtelomeric regions of host cell chromosomes.…”

Section: Discussionmentioning

confidence: 99%

Complete Unique Genome Sequence, Expression Profile, and Salivary Gland Tissue Tropism of the Herpesvirus 7 Homolog in Pigtailed Macaques

Staheli

Dyen

Deutsch

et al. 2016

J Virol

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Human herpesvirus 6A (HHV-6A), HHV-6B, and HHV-7 are classified as roseoloviruses and are highly prevalent in the human population. Roseolovirus reactivation in an immunocompromised host can cause severe pathologies. While the pathogenic potential of HHV-7 is unclear, it can reactivate HHV-6 from latency and thus contributes to severe pathological conditions associated with HHV-6. Because of the ubiquitous nature of roseoloviruses, their roles in such interactions and the resulting pathological consequences have been difficult to study. Furthermore, the lack of a relevant animal model for HHV-7 infection has hindered a better understanding of its contribution to roseolovirus-associated diseases. Using next-generation sequencing analysis, we characterized the unique genome of an uncultured novel pigtailed macaque roseolovirus. Detailed genomic analysis revealed the presence of gene homologs to all 84 known HHV-7 open reading frames. Phylogenetic analysis confirmed that the virus is a macaque homolog of HHV-7, which we have provisionally named Macaca nemestrina herpesvirus 7 (MneHV7). Using high-throughput RNA sequencing, we observed that the salivary gland tissue samples from nine different macaques had distinct MneHV7 gene expression patterns and that the overall number of viral transcripts correlated with viral loads in parotid gland tissue and saliva. Immunohistochemistry staining confirmed that, like HHV-7, MneHV7 exhibits a natural tropism for salivary gland ductal cells. We also observed staining for MneHV7 in peripheral nerve ganglia present in salivary gland tissues, suggesting that HHV-7 may also have a tropism for the peripheral nervous system. Our data demonstrate that MneHV7-infected macaques represent a relevant animal model that may help clarify the causality between roseolovirus reactivation and diseases.IMPORTANCE Human herpesvirus 6A (HHV-6A), HHV-6B, and HHV-7 are classified as roseoloviruses. We have recently discovered that pigtailed macaques are naturally infected with viral homologs of HHV-6 and HHV-7, which we provisionally named MneHV6 and MneHV7, respectively. In this study, we confirm that MneHV7 is genetically and biologically similar to its human counterpart, HHV-7. We determined the complete unique MneHV7 genome sequence and provide a comprehensive annotation of all genes. We also characterized viral transcription profiles in salivary glands from naturally infected macaques. We show that broad transcriptional activity across most of the viral genome is associated with high viral loads in infected parotid glands and that late viral protein expression is detected in salivary duct cells and peripheral nerve ganglia. Our study provides new insights into the natural behavior of an extremely prevalent virus and establishes a basis for subsequent investigations of the mechanisms that cause HHV-7 reactivation and associated disease.

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“…The HHV-6A/B genome consists of a single unique component (U) (∼145 kbp) flanked by identical direct repeats (DR) (∼9 kbp) ( 14 – 17 ) that are flanked by the cleavage and packaging signals pac1 and pac2 ( 18 , 19 ). Adjacent to the pac2 sequences are arrays of TTAGGG repeats that are identical to the human telomeric repeat sequence (TRS).…”

Section: Introductionmentioning

confidence: 99%

Characterization of human herpesvirus 6A/B U94 as ATPase, helicase, exonuclease and DNA-binding proteins

Trempe¹,

Gravel²,

Dubuc³

et al. 2015

Nucleic Acids Res

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Human herpesvirus-6A (HHV-6A) and HHV-6B integrate their genomes into the telomeres of human chromosomes, however, the mechanisms leading to integration remain unknown. HHV-6A/B encode a protein that has been proposed to be involved in integration termed U94, an ortholog of adeno-associated virus type 2 (AAV-2) Rep68 integrase. In this report, we addressed whether purified recombinant maltose-binding protein (MBP)-U94 fusion proteins of HHV-6A/B possess biological functions compatible with viral integration. We could demonstrate that MBP-U94 efficiently binds both dsDNA and ssDNA containing telomeric repeats using gel shift assay and surface plasmon resonance. MBP-U94 is also able to hydrolyze adenosine triphosphate (ATP) to ADP, providing the energy for further catalytic activities. In addition, U94 displays a 3′ to 5′ exonuclease activity on dsDNA with a preference for 3′-recessed ends. Once the DNA strand reaches 8–10 nt in length, the enzyme dissociates it from the complementary strand. Lastly, MBP-U94 compromises the integrity of a synthetic telomeric D-loop through exonuclease attack at the 3′ end of the invading strand. The preferential DNA binding of MBP-U94 to telomeric sequences, its ability to hydrolyze ATP and its exonuclease/helicase activities suggest that U94 possesses all functions required for HHV-6A/B chromosomal integration.

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Functional Identification and Analysis of cis -Acting Sequences Which Mediate Genome Cleavage and Packaging in Human Herpesvirus 6

Cited by 37 publications

References 37 publications

Human Herpesvirus 6B Genome Sequence: Coding Content and Comparison with Human Herpesvirus 6A

Human Herpesvirus 6B Genome Sequence: Coding Content and Comparison with Human Herpesvirus 6A

Complete Unique Genome Sequence, Expression Profile, and Salivary Gland Tissue Tropism of the Herpesvirus 7 Homolog in Pigtailed Macaques

Characterization of human herpesvirus 6A/B U94 as ATPase, helicase, exonuclease and DNA-binding proteins

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