The molecular biology of human herpesvirus-6 latency and telomere integration

Abstract

The genomes of herpesviruses establish latency as a circular episome. However, Human herpesvirus-6 (HHV-6) has been shown to specifically integrate into the telomeres of chromosomes during latency and vertically transmit through the germ-line. This review will focus on the telomere integration of HHV-6, the potential viral and cellular genes that mediate integration, and the clinical impact on the host.

Fig. 1

Schematic comparing the genome structure of HHV-6 to germ-line-integrated HHV-6. (gliHHV-6). (a) The linear HHV-6 genome contains a unique long (U_L) region of 13–160 kb with left and right direct repeats (DR) of 7–8 kb at the termini. Perfect and imperfect telomere sequence (TTAGGG) positioned at end of DR play role HHV-6 chromosome integration into the telomere. (b) Fluorescence in situ hybridization (FISH) of PBMCs from a patient with gliHHV-6A integrated into the telomere of chromosome 22q. Metaphase chromosomes counterstained with DAPI (blue), cy5-PNA telomere probe (red), and FITC-conjugated HHV-6 cosmid probe (green). (c) Genome structure of gliHHV-6 in which HHV-6 DR_R is fused with the telomere repeats near the chromosome subtelomere and the DR_L fused with the remaining telomere repeat array (TTAGGG)_n [19].

Fig. 2

Proposed model of HHV-6 integration into chromosome telomeres. (a) We hypothesizes that localization of the linear HHV-6 genome to chromosome telomeres occurs through TRF2 and TRF1 bidding of chromosome and HHV-6 DR encoded telomere repeat. (b) The viral rep gene ORF U94 then promotes homologous recombination between viral and chromosome telomere repeats, (c) which results in the integration of HHV-6 into chromosome telomeres.

Fig. 3

Structural SWISS-MODEL and consensus sequence of HHV-6A ORF U94 N and C-terminus. (a) The predicted ribbon diagrams of the U94 N-terminus (15–206 aa) corresponds to the AAV rep nuclease domain [Protein Data Bank (PDB) accession number 1uut [76]) and the (b) C-terminus (229–490 aa) of U94 corresponds to the AAV rep helicase domain [PDB accession number 1s9h [78]] circled in blue. (c) Consensus protein sequence of AAV-2 Rep78 illustrates the DNA-binding domain (DBD) and endonuclease (Endo) domain for the N-terminus of HHV-6A ORF U94. (d) The consensus protein sequence of AAV-2 Rep40 helicase domain and C-terminus of HHV-6A U94. The Walker (A, B, B’, and C) motifs form the core of the SF3 helicase and the arginine (Arg) finger catalyzes ATP hydrolysis when the protein forms a hexamer structure.