HHV-6A/B Integration and the Pathogenesis Associated with the Reactivation of Chromosomally Integrated HHV-6A/B

Abstract

Unlike other human herpesviruses, human herpesvirus 6A and 6B (HHV-6A/B) infection can lead to integration of the viral genome in human chromosomes. When integration occurs in germinal cells, the integrated HHV-6A/B genome can be transmitted to 50% of descendants. Such individuals, carrying one copy of the HHV-6A/B genome in every cell, are referred to as having inherited chromosomally-integrated HHV-6A/B (iciHHV-6) and represent approximately 1% of the world's population. Interestingly, HHV-6A/B integrate their genomes in a specific region of the chromosomes known as telomeres. Telomeres are located at chromosomes' ends and play essential roles in chromosomal stability and the long-term proliferative potential of cells. Considering that the integrated HHV-6A/B genome is mostly intact without any gross rearrangements or deletions, integration is likely used for viral maintenance into host cells. Knowing the roles played by telomeres in cellular homeostasis, viral integration in such structure is not likely to be without consequences. At present, the mechanisms and factors involved in HHV-6A/B integration remain poorly defined. In this review, we detail the potential biological and medical impacts of HHV-6A/B integration as well as the possible chromosomal integration and viral excision processes.

Keywords: human herpesvirus 6A/B; inherited chromosomally-integrated HHV-6A/B; integration; reactivation; telomere.

Figure 1

HHV-6A/B genomes and their integrated forms. Schematic representation of human herpesvirus 6A and 6B (HHV-6A/B) genomes and the reported integrated forms. (A) The unique region (U) of the 160 kbp HHV-6A/B genomes is flanked by identical direct repeats (DR_L and DR_R) of 8–9 kbp. The DRs possess a pac1 (yellow) and pac2 (red) sequences, adjacent to imperfect telomeric repeats impTMR (blue) and TMR (green) sequences, respectively. The genome is not drawn to scale; (B) Chromosomally integrated HHV-6A/B (ciHHV-6A/B) genome (with loss of pac2 in DR_R and pac1 in DR_L) with elongated telomeres at the DR_L; (C) Single integrated DR_L with elongated telomere; (D) Integrated HHV-6A/B concatemers. Genomes are not drawn to scale.

Figure 2

Possible mechanisms of HHV-6A/B genome excision from telomeres. Schematic representation of hypothetic processes of HHV-6A/B genome excision from telomeres. (A) Telomeric repeats form a t-loop in the TMR of HHV-6A/B DR_L, followed by recombination and excision, resulting into a first t-loop excision: a telomeric circle and a chromosomally integrated HHV-6A/B lacking a DR but still possessing TMR sequences. (B) A second t-loop formation is made by recombination of the TMR at the end of the genome into HHV-6A/B DR_R, resulting in a fully excised and circular HHV-6A/B genome containing a single DR with a single pac1, pac2, impTMR and TMR sequence. (C) Invasion of the telomeric repeats into the TMR of the DR_R, resulting into a HHV-6A/B free chromosome and a full viral genome with a complete DR.

Figure 3

Possible mechanisms for HHV-6A/B integration. Schematic representation of HHV-6A/B chromosomal integration process. (A) Unfolding of the chromosome t-loop and invasion by the telomeric 3′ overhang into HHV-6A/B’s DR. This mechanism is unlikely to occur since all ciHHV-6A/B reported so far have lost most telomeric repeats. (B) Break induced replication (BIR) repair mechanism caused by G quadruplexes (G4) structure (or other blockage) in the lagging strand. (C) The free 3′ strand is rescued by Rad51 protein that searches for proximal homologous sequences. If a HHV-6A/B genome is close to proximity, Rad51 invades the viral TMR, displacing one strand of the HHV-6A/B genome to allow the synthesis of the complementary strand. Upon cell divisions, the DR_L would lose pac1 due to end replication problem and the impTMR would serve as telomeric template to elongate telomeres at the end of the genome. (D) Single stranded annealing (SSA) repair mechanism. Upon virus entry in the cell, DNA damage response is triggered, at the same time a break caused by a stalled replication fork at the human telomeres activate SSA. SSA activation leads to resection of both the viral and human DNA in a 5′ to 3′ direction to create complementary sequences. Meanwhile, the 3′ strands of both genomes are protected by the replication protein A (RPA). Rasd52 binds the RPA and searched for pairing in which pac2 will be lost. Annealed sequences then lead to the copying of the viral genome. Genomes are not drawn to scale.