The mechanism and significance of integration and vertical transmission of human herpesvirus 6 genome

Abstract

The integration of HHV-6 into telomeres is a newly identified form of Human Herpesvirus latency. The integration of iHHV-6A and iHHV-6B into the same chromosome telomeres of family members lends itself to vertical transmission through the germ-line. Studies have shown that iHHV-6A and iHHV-6B preferentially integrated in chromosomes' telomeres 9q34.4, 17p13.3, 18q23, 19q13.4, and 22q13.3. Congenital or connatal HHV-6 infection occurs in up to 1% of infants and may be due to either transplacental infection or vertical transmission of the integrated virus. The humoral response to a primary HHV-6 infection differs from that to iHHV-6. A primary response leads to the production of anti-HHV-6 IgM and IgG antibodies, while only IgG antibodies have been detected in the serum of iHHV-6 patients. Evidence for immune tolerance and an altered immune response to HHV-6 have been detected, too. The presence of anti-IE-1 antibodies may indicate viral reactivation in iHHV-6 carriers. In normal healthy blood donors it was found that 0.8-1.0% had high viral loads most likely attributed to iHHV-6 integration in the germ-line. The prevalence of integrated iHHV-6 in hospitalized patients was higher, 2.9-3.3%. Will clinicians also have to consider screening for iHHV-6 during blood donations? It is yet unknown whether the integrated latent virus of the donor is capable of reactivation and subsequently infecting cells of the recipient resulting in possible pathological consequences. Future studies are required to determine the overall impact of the integrated virus whether it may have harmful effects on hospitalized patients and understand disease progression associated with iHHV-6. The full length genome of EBV infrequently integrates into random chromosome sites during latency. The gammaherpesvirus Marek's Disease Virus (MDV) frequently integrates into the telomere of chickens through telomeric repeats. Of the six shelterin proteins, TRF2 was shown to bind to the three nonamer EBV encoded TTAGGGTTA repeat within the origin of latent DNA replication (oriP) in cooperation with viral latency gene EBNA-1. It is hypothesized by the authors that the binding of telomere repeats encoded in the DR of HHV-6 by TRF2/TRF1 plays a role in telomere mediated integration by facilitating the localization of the viral genome to the telomere of chromosomes. It is suggested, that ORF U94 may function as a latency gene and possibly facilitate HHV-6A/HHV-6B specific integration into telomeres similar to its AAV-2 encoded rep68/78 counterpart. The integration of HHV-6 into chromosomes is not a dead end pathway; the virus is shown to reactivate from its latent integrated state and leads to infection of naïve cells resulting in cell death. It is proposed that integration of HHV-6 into the telomere of chromosomes occurs through homologous recombination. However, it remains unknown whether the viral latency gene ORF U94 and telomere binding proteins TRF1 and TRF2 do in fact play a role during the process of integration. Furthermore, the physiological effect and impact on the stability of iHHV-6 has on the telomere remains unknown.