Human herpesvirus 6 integrates within telomeric regions as evidenced by five different chromosomal Sites

Nacheva, Elisabeth P.; Ward, Katherine N.; Brazma, Diana; Virgili, Anna; Howard, Julie; Leong, Hoe Nam; Clark, Duncan A.

doi:10.1002/jmv.21299

Cited by 94 publications

(84 citation statements)

References 37 publications

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“…Previous research has identified occasional patients with high copy numbers of HHV-6 DNA and FISH results suggesting chromosome integrated HHV-6 (19)(20)(21)(22)(23)(24)(25). Often the same findings occur in both parents and children, suggesting vertical transmission in the germline.…”

Section: Resultsmentioning

confidence: 89%

“…However, some studies using FISH analysis have suggested that both HHV-6A and B can integrate into human chromosomes (19)(20)(21)(22)(23)(24)(25) and may be vertically transmitted in the germ line (26). FISH assay, however, cannot distinguish noncovalent linkage from integration, establish the specific integration site, or determine whether the integrated virus can reactivate and produce infectious virions.…”

mentioning

confidence: 99%

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The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro

Arbuckle

Medveczky

Luka³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

314

398

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Previous research has suggested that human herpesvirus-6 (HHV-6) may integrate into host cell chromosomes and be vertically transmitted in the germ line, but the evidence-primarily fluorescence in situ hybridization (FISH)-is indirect. We sought, first, to definitively test these two hypotheses. Peripheral blood mononuclear cells (PBMCs) were isolated from families in which several members, including at least one parent and child, had unusually high copy numbers of HHV-6 DNA per milliliter of blood. FISH confirmed that HHV-6 DNA colocalized with telomeric regions of one allele on chromosomes 17p13.3, 18q23, and 22q13.3, and that the integration site was identical among members of the same family. Integration of the HHV-6 genome into TTAGGG telomere repeats was confirmed by additional methods and sequencing of the integration site. Partial sequencing of the viral genome identified the same integrated HHV-6A strain within members of families, confirming vertical transmission of the viral genome. We next asked whether HHV-6A infection of naïve cell lines could lead to integration. Following infection of naïve Jjhan and HEK-293 cell lines by HHV-6, the virus integrated into telomeres. Reactivation of integrated HHV-6A virus from individuals' PBMCs as well as cell lines was successfully accomplished by compounds known to induce latent herpesvirus replication. Finally, no circular episomal forms were detected even by PCR. Taken together, the data suggest that HHV-6 is unique among human herpesviruses: it specifically and efficiently integrates into telomeres of chromosomes during latency rather than forming episomes, and the integrated viral genome is capable of producing virions.

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Section: Resultsmentioning

confidence: 89%

mentioning

confidence: 99%

The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro

Arbuckle

Medveczky

Luka³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

314

398

View full text Add to dashboard Cite

show abstract

“…HHV-6A/B integration can occur in various chromosomes, with viral genomes consistently detected in telomeric regions that are located at chromosome termini (5,10,(13)(14)(15). Telomeres are composed of double-stranded TTAGGG repeats (8 to 13 kbp long) followed by a 30-to 200-bp single-stranded 3= overhang (16)(17)(18)(19).…”

mentioning

confidence: 99%

Stabilization of Telomere G-Quadruplexes Interferes with Human Herpesvirus 6A Chromosomal Integration

Gilbert-Girard

Gravel

Artusi

et al. 2017

J Virol

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Human herpesviruses 6A and 6B (HHV-6A/B) can integrate their genomes into the telomeres of human chromosomes using a mechanism that remains poorly understood. To achieve a better understanding of the HHV-6A/B integration mechanism, we made use of BRACO-19, a compound that stabilizes G-quadruplex secondary structures and prevents telomere elongation by the telomerase complex. First, we analyzed the folding of telomeric sequences into G-quadruplex structures and their binding to BRACO-19 using G-quadruplex-specific antibodies and surface plasmon resonance. Circular dichroism studies indicate that BRACO-19 modifies the conformation and greatly stabilizes the G-quadruplexes formed in G-rich telomeric DNA. Subsequently we assessed the effects of BRACO-19 on the HHV-6A initial phase of infection. Our results indicate that BRACO-19 does not affect entry of HHV-6A DNA into cells. We next investigated if stabilization of G-quadruplexes by BRACO-19 affected HHV-6A's ability to integrate its genome into host chromosomes. Incubation of telomerase-expressing cells with BRACO-19, such as HeLa and MCF-7, caused a significant reduction in the HHV-6A integration frequency (P Ͻ 0.002); in contrast, BRACO-19 had no effect on HHV-6 integration frequency in U2OS cells that lack telomerase activity and elongate their telomeres through alternative lengthening mechanisms. Our data suggest that the fluidity of telomeres is important for efficient chromosomal integration of HHV-6A and that interference with telomerase activity negatively affects the generation of cellular clones containing integrated HHV-6A.IMPORTANCE HHV-6A/B can integrate their genomes into the telomeres of infected cells. Telomeres consist of repeated hexanucleotides (TTAGGG) of various lengths (up to several kilobases) and end with a single-stranded 3= extension. To avoid recognition and induce a DNA damage response, the single-stranded overhang folds back on itself and forms a telomeric loop (T-loop) or adopts a tertiary structure, referred to as a G-quadruplex. In the current study, we have examined the effects of a G-quadruplex binding and stabilizing agent, BRACO-19, on HHV-6A chromosomal integration. By stabilizing G-quadruplex structures, BRACO-19 affects the ability of the telomerase complex to elongate telomeres. Our results indicate that BRACO-19 reduces the number of clones harboring integrated HHV-6A. This study is the first of its kind and suggests that telomerase activity is essential to restore a functional telomere of adequate length following HHV-6A integration.

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“…9,10 HHV-6 is unique among the human herpesviruses in that the whole viral genome is integrated into one of several different human chromosomes at the telomere in 0.2% to 0.8% of the population and passed from parent to child in the germline via Mendelian inheritance. 11,12 The clinical relevance of congenital infection with HHV-6 is undefined but may be similar to CMV and associated with developmental disability.…”

mentioning

confidence: 99%

Early Developmental Outcomes of Children With Congenital HHV-6 Infection

Caserta¹,

Hall²,

Canfield

et al. 2014

Pediatrics

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OBJECTIVE: The goal of this study was to determine if congenital human herpesvirus-6 (HHV-6) infection influences early neurodevelopment. METHODS: We enrolled 57 newborns with HHV-6 congenital infection and 242 control newborns without congenital infection into a prospective, double-blind study with 4 visits between 4 and 30 months of age. Assessments included the Fagan Test of Infant Intelligence, the Visual Expectation Paradigm, and the Mental Development Index (MDI) of the Bayley Scales of Infant Development II. Newborn audiology screening and follow-up audiology examinations were completed at 12 to 24 months. RESULTS: No differences were noted in baseline characteristics between infants with HHV-6 congenital infection and control infants. No clinical syndrome due to congenital infection with HHV-6 was evident at birth. No differences were identified on the Fagan Test of Infant Intelligence or the Visual Expectation Paradigm between the two groups. In 39 infants with HHV-6 congenital infection, the mean ± SD Bayley Scale of Infant Development II MDI score was 103.4 ± 8.9 at 12 months of age. The matched control infants had a mean score of 105.4 ± 12.4. After controlling for covariates, HHV-6 congenital infection was associated with lower scores on the Bayley Scale of Infant Development II MDI at 12 months of age (mean difference: 4.3 [95% confidence interval: 0.4 to 8.1]; P = .03) compared with infants without HHV-6 congenital infection. CONCLUSIONS: Congenital HHV-6 infection may have a detrimental effect on neurodevelopment at 12 months of age and requires further study given that congenital infection with HHV-6 is present in ∼1 in every 101 births.

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Human herpesvirus 6 integrates within telomeric regions as evidenced by five different chromosomal Sites

Cited by 94 publications

References 37 publications

The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro

The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro

Stabilization of Telomere G-Quadruplexes Interferes with Human Herpesvirus 6A Chromosomal Integration

Early Developmental Outcomes of Children With Congenital HHV-6 Infection

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