Chromosomally integrated human herpes virus 6 (Cl-HHV6) disrupts telomere stability and favors release of functional viruses.

Each end of chromatid contains a region of repetitive nucleotide sequences that guard deterioration of chromosomes. This region is known as telomere and aids in prevention of shortening of chromosomes during the process of replication. A protein complex termed as Shelterin binds via TRF1/2 and POT 1 to telomeric DNA to prevent inappropriate recombination repair events. The length of telomeres is varied among different species and is generally composed of guanine rich residue repeats. Telomere loops or T-loops are formed at the ends due to ss-DNA curls stabilized by proteins. Telomeres are shortened in almost all cancers and tumors.

Human Herpes Virus 6 (HHV6), which is a collective name for two sub families HHV 6A and HHV 6B, is one of the most common cause of “sixth disease” or “roseola infantum”, that occurs in infants. An important feature of HHV6 is that it can integrate into human telomeric DNA. This process is achieved by right direct repeat (DRr) of the virus. Once integrated, this virus can inherit itself into the germline of an organism. About 1% of population inherits a chromosomally integrated human herpes virus 6 (Cl-HHV6) and less is known regarding the effects of this integration on the telomere length and function.

Recently a research team at the Department of Genetics, University of Leicester, UK, tried to determine whether integration of HHV6 is a biological form of latency or not and how does its association affect the telomere or telomere length in carriers of HHV6? While looking for the answers the researchers of this study have established that T1 region has a role in erosion process that aids in the loss of PAC1 and DRl-T1 region until telomere repeats are added in the germline. The virus associated telomere is readily lengthened by telomerase in the germline. Cl-HHV6 associated telomere is one of the shortest in somatic cells. It is more prone to deletions and truncations that cause manufacture of short telomere at the new spot in the viral genome.

About 1178 samples from HapMap Phase I, the CEPH-HGDP and the CEPH family panels, 528 samples from the People of the British Isles panel, 2153 samples from the Orkney Complex Disease Study and 92 sperm DNA samples were analyzed in this study for identification of CL-HHV6 carriers.

In case of 92 sperm DNA samples that were tested to scrutinize virus-associated telomere lengths in the germline, it was found that proportion of outlier molecules was considerably shorter than the mean length and this shortening outcome was likely due to t-loop erasure. Single telomere length analysis (STELA) was used for measuring the telomere lengths. Moreover, telomere capping is affected by HHV6 via t-loop formation. The integrated copies of HHV6B can be excised via t-loop formation and it could be one of the preliminary steps towards reactivation of virus for spread to new locations in the cell. In-fact the authors have detected that within Cl-HHV6 genome extra-chromosomal and truncated CL-HHV6 molecules are present that are responsible for disruption of telomere stability. Thus, Instability and replicative senescence, due to fusion events, are more likely to occur in cells carrying short telomerase associated with Cl-HHV6.

Overall in wrapping up, this study has proved it that HHV6 latency is as a result of telomeric integration.

Reference:

Yan Huang, Alberto Hidalgo-Bravo, Enjie Zhang, Victoria E. Cotton, Aaron Mendez-Bermudez, Gunjan Wig, Zahara Medina-Calzada, Rita Neumann, Alec J. Jeffreys, Bruce Winney, James F. Wilson, Duncan A. Clark, Martin J. Dyer, and Nicola J. Royle. Human telomeres that carry an integrated copy of human herpesvirus 6 are often short and unstable, facilitating release of the viral genome from the chromosome. Nucleic Acids Res. 2014 January; 42(1): 315–327. doi:  10.1093/nar/gkt840

This is an OA article under creativecommons.org/licenses/by/3.0/

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