Mapping the telomere integrated genome of human herpesvirus 6A and 6B

Arbuckle, Jesse H.; Pantry, Shara N.; Medveczky, Maria M.; Prichett, Joshua; Loomis, Kristin S.; Ablashi, Dharam V.; Medveczky, Peter G.

doi:10.1016/j.virol.2013.03.030

Cited by 66 publications

(69 citation statements)

References 42 publications

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“…Analysis of the integrated virus genome revealed that the perfect TMR of the DR R region are fused to the host chromosome accompanied by a loss of the pac2 sequence, consistent with an integration mediated by HR between the viral TMR and the host telomere (5). At the other end of the viral genome, the pac1 region is also lost and additional telomeric repeats are added, suggesting that the TMR in DR L is a substrate for the generation of a new telomere (29)(30)(31).…”

mentioning

confidence: 78%

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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mentioning

confidence: 78%

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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“…These repeated sequences likely play a major role in the process of chromosomal integration of the HHV-6 genome (ciHHV-6) (see below). This integration has been reported to occur through a junction between host chromosomes and the perfect telomeric repeats at the right end of DR R (23)(24)(25). The overall number of protein-encoding open reading frames (ORFs) is about 110 to 120 according to the different published nucleotide sequences (26)(27)(28).…”

Section: Genome and Genetic Variabilitymentioning

confidence: 99%

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

2015

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SUMMARY Human herpesvirus 6 (HHV-6) is a widespread betaherpesvirus which is genetically related to human cytomegalovirus (HCMV) and now encompasses two different species: HHV-6A and HHV-6B. HHV-6 exhibits a wide cell tropism in vivo and, like other herpesviruses, induces a lifelong latent infection in humans. As a noticeable difference with respect to other human herpesviruses, genomic HHV-6 DNA is covalently integrated into the subtelomeric region of cell chromosomes (ciHHV-6) in about 1% of the general population. Although it is infrequent, this may be a confounding factor for the diagnosis of active viral infection. The diagnosis of HHV-6 infection is performed by both serologic and direct methods. The most prominent technique is the quantification of viral DNA in blood, other body fluids, and organs by means of real-time PCR. Many active HHV-6 infections, corresponding to primary infections, reactivations, or exogenous reinfections, are asymptomatic. However, the virus may be the cause of serious diseases, particularly in immunocompromised individuals. As emblematic examples of HHV-6 pathogenicity, exanthema subitum, a benign disease of infancy, is associated with primary infection, whereas further virus reactivations can induce severe encephalitis cases, particularly in hematopoietic stem cell transplant recipients. Generally speaking, the formal demonstration of the causative role of HHV-6 in many acute and chronic human diseases is difficult due to the ubiquitous nature of the virus, chronicity of infection, existence of two distinct species, and limitations of current investigational tools. The antiviral compounds ganciclovir, foscarnet, and cidofovir are effective against active HHV-6 infections, but the indications for treatment, as well as the conditions of drug administration, are not formally approved to date. There are still numerous pending questions about HHV-6 which should stimulate future research works on the pathophysiology, diagnosis, and therapy of this remarkable human virus.

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“…All three human roseoloviruses contain mammalian telomeric sequences at their genomic termini, and telomeres are the site of integration of HHV-6A and HHV-6B in patients with chromosomally integrated HHV-6 [36,37]. Telomeric integration occurs in infected cultured Jjhan and HEK-293 cells, establishing a system for mapping and characterizing the mechanistic processes of integration.…”

Section: Latency and Reactivationmentioning

confidence: 99%

“…If integration is a mechanism of latency, a functional virus genome must be excised from telomeres in order to reactivate full lytic infection. HEK293 cells with integrated HHV-6A can produce viral genome concatamers upon treatment with the histone deacetylase inhibitor trichostatin A [36]. Huang et al [43] noted that the telomeres attached to integrated HHV-6 genomes are frequently shortened and associated with detection of circular viral genomes.…”

Section: Latency and Reactivationmentioning

confidence: 99%

Roseolovirus molecular biology: recent advances

Krug

Pellett

2014

Current Opinion in Virology

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Human herpesviruses 6A, −6B, and −7 (HHV-6A, −6B, and −7) are classified within the roseolovirus genus of the betaherpesvrus subfamily. Most humans likely harbor at least two of these large DNA viruses, and 1% of humans harbor germline chromosomally integrated HHV-6A or HHV-6B genomes. Differences at the genetic level manifest as distinct biologic properties during infection and disease. We provide a brief synopsis of roseolovirus replication and highlight the unique properties of their lifecycle and what is known about the viral gene products that mediate these functions. In the nearly 30 years since their discovery, we have only begun to unlock the molecular strategies these highly evolved pathogens employ to establish and maintain chronic infections in humans.

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Mapping the telomere integrated genome of human herpesvirus 6A and 6B

Cited by 66 publications

References 42 publications

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

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

Laboratory and Clinical Aspects of Human Herpesvirus 6 Infections

Roseolovirus molecular biology: recent advances

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