The DNA Sequence of Human Herpesvirus-6: Structure, Coding Content, and Genome Evolution

Abstract

The complete DNA sequence was determined for strain U1102 of human herpesvirus-6, a CD4+ T-lymphotropic virus with disease associations in immunodeficient settings and a possible complicating factor in AIDS. The genome is 159,321 bp in size, has a base composition of 43% G + C, and contains 119 open reading frames. The overall structure is 143 kb bounded by 8 kb of direct repeats, DRL (left) and DRR (right), containing 0.35 kb of terminal and junctional arrays of human telomere-like simple repeats. Since eight open reading frames are duplicated in the repeats, six span repetitive elements and three are spliced, the genome is considered to contain 102 separate genes likely to encode protein. The genes are arranged colinearly with those in the genome of the previously sequenced betaherpesvirus, human cytomegalovirus, and has a distinct arrangement of conserved genes relative to the sequenced gammaherpesviruses, herpesvirus saimiri and Epstein-Barr virus, and the alphaherpesviruses, equine herpesvirus-1, varicella-zoster virus, and herpes simplex virus. Comparisons of predicted amino acid sequences allowed the functions of many human herpesvirus-6 encoded proteins to be assigned and showed the closest relationship in overall number and similarity to human cytomegalovirus products, with approximately 67% homologous proteins as compared to the 21% identified in all herpesviruses. The features of the conserved genes and their relative order suggested a general scheme for divergence among these herpesvirus lineages. In addition to the "core" conserved genes, the genome contains four distinct gene families which may be involved in immune evasion and persistence in immune cells: two have similarity to the "chemokine" chemotactic/proinflammatory family of cytokines, one to their peptide G-protein-coupled receptors, and a fourth to the immunoglobulin superfamily.

Human Herpesvirus 6 DNA Levels in Cerebrospinal Fluid Due to Primary Infection Differ from Those Due to Chromosomal Viral Integration and Have Implications for Diagnosis of Encephalitis

“…Five microliters of DNA extract from whole blood, serum, or CSF was subjected to quantitative HHV-6 PCR, and the result was compared with the result of quantitative PCR for human ␤-globin (25). The HHV-6 PCR (8) amplifies DNA from part of the HHV-6 U67 gene, of which there is only one copy per virus genome (16). Since there are 2 copies of ␤-globin/cell, the number of viral DNA copies/cell is 2 ϫ HHV-6 DNA copies/␤-globin DNA copies (46).…”

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

“…The HHV-6A/B genome consists of a unique sequence (U) that is flanked by G-rich direct repeat regions (DR) that harbor the packaging sequences (pac1 and pac2) and two arrays of either perfect or imperfect telomeric repeats (TMR) at the genome termini (22)(23)(24)(25)(26). The presence of these repeats at the ends of the viral genomes and the fact that chromosomal integration occurs in telomeres led to the hypothesis that HHV-6A/B integrates the human genome by homologous recombination (HR) between viral TMRs and chromosomal telomeric sequences (10,27).…”

Deletion of the R78 G protein-coupled receptor gene from rat cytomegalovirus results in an attenuated, syncytium-inducing mutant strain

“…Additionally, some are encoded by virus genes. To date, 20 putative viral GCR genes have been discovered: 2 in poxvirus genomes (21,44), 11 in betaherpesvirus genomes (9,22,33,49,54), and 7 in gammaherpesvirus genomes (4,26,48,57,63). The majority of these genes was found to be similar to genes encoding cellular chemokine receptors.…”

“…The KSHV chemokine receptor was also shown to stimulate cellular proliferation (4), transformation, and angiogenesis (7). A distinctive set of chemokine-like receptors is exclusively encoded by betaherpesviruses: HCMV UL33 (23), rat cytomegalovirus (RCMV) R33 (9), murine cytomegalovirus (MCMV) M33 (54), and human herpesvirus 6 and 7 (HHV-6 and -7) U12 (33,49). Recently, we found that the RCMV R33 gene is essential for the pathogenesis of viral infection in vivo and that unlike wild-type (wt) virus, an RCMV R33 null mutant could neither enter nor replicate in salivary gland epithelial cells of infected rats (9).…”

“…A similar observation was made for MCMV M33: upon infection of mice with an MCMV M33 deletion mutant strain, virus could not be recovered from mouse salivary glands (26). Interestingly, betaherpesviruses encode another distinctive set of yet uncharacterized viral GCRs: HCMV UL78 (22), MCMV M78 (54), and HHV-6 and -7 U51 (33,49). Although the positions of these UL78-like genes within the betaherpesvirus genomes are conserved, their sequences are rather divergent.…”