Update on human herpesvirus 6 biology, clinical features, and therapy

Abstract

Human herpesvirus 6 (HHV-6) is a betaherpesvirus that is closely related to human cytomegalovirus. It was discovered in 1986, and HHV-6 literature has expanded considerably in the past 10 years. We here present an up-to-date and complete overview of the recent developments concerning HHV-6 biological features, clinical associations, and therapeutic approaches. HHV-6 gene expression regulation and gene products have been systematically characterized, and the multiple interactions between HHV-6 and the host immune system have been explored. Moreover, the discovery of the cellular receptor for HHV-6, CD46, has shed a new light on HHV-6 cell tropism. Furthermore, the in vitro interactions between HHV-6 and other viruses, particularly human immunodeficiency virus, and their relevance for the in vivo situation are discussed, as well as the transactivating capacities of several HHV-6 proteins. The insight into the clinical spectrum of HHV-6 is still evolving and, apart from being recognized as a major pathogen in transplant recipients (as exemplified by the rising number of prospective clinical studies), its role in central nervous system disease has become increasingly apparent. Finally, we present an overview of therapeutic options for HHV-6 therapy (including modes of action and resistance mechanisms).

FIG. 1.

Schematic representation of the HHV-6B genomic organization. The terminal direct repeats (DR_L and DR_R) are boxed, and the intermediate repeats (R1, R2, and R3) are shown as red boxes. Telomeric sequences (T1 and T2) are denoted as green bars. The origin of lytic replication (Ori) is indicated by an asterisk. Protein coding regions are represented by open arrows; arrows colored yellow denote genes belonging to the HCMV US22 gene family. GCR, G-protein-coupled receptor; Ig, immunoglobulin superfamily; RR, ribonucleotide reductase; mCP, minor capsid protein; CA, capsid assembly protein; Teg, large tegument protein; Pol, DNA polymerase; tp, transport protein; mDBP, major single-stranded DNA binding protein; TA, conserved herpesvirus transactivator; dUT, dUTPase; Pts, protease/assembly protein; MCP, major capsid protein; PT, phosphotransferase; Exo, exonuclease; OBP, origin binding protein; Hel, helicase; UDG, uracil-DNA glycosylase; Che, chemokine; AAV/rep, adeno-associated virus-2 replication protein homolog. Reproduced from Isegawa et al. (183) with permission of the publisher.

FIG. 2.

Schematic representation of the HHV-6 lytic replication cycle. The successive events of entry, replication, maturation, and egress are described in detail in “Replication cycle” in the text.

FIG. 3.

Schematic diagram of the HHV-6A IE-A region. The region encodes two proteins (termed IE1 and IE2), which correspond to the open reading frames U90-89 and U90-86/87, respectively. Reproduced from reference with permission of the publisher.

FIG. 4.

Chemical structures of clinically used anti-HHV-6 compounds.

FIG. 5.

Metabolic activation of acyclic nucleoside analogs (exemplified by ganciclovir) and acyclic nucleoside phosphonates (represented by cidofovir). Abbreviations are explained in the text in “Ganciclovir and acyclovir” and “Cidofovir.”

FIG. 6.

ClustalW alignment of the HHV-6 pU69 and HCMV pUL97 protein sequences. The overall identity between HHV-6 GS and Z29 pU69 proteins is 94%. Identical residues are indicated by an asterisk. The colons and periods represent strong and weak functional similarities, respectively. Published mutations conferring ganciclovir phenotypic resistance (74, 277, 356) are boxed. Conserved domains are shaded. Amino acid residues that are highly conserved in protein kinases are highlighted within conserved domains. The GXGXXG motif thus indicated in domains I and II is the putative nucleotide binding site. The (A)ACR(AL) motif at amino acid positions 590 to 595 in pUL97 is essential for ganciclovir phosphorylation (381) and is among protein kinases unique to HHV-6 and HCMV.

FIG. 7.

Schematic representation of HCMV (A) and HHV-6 (B) DNA polymerases. Conserved regions are boxed. Functional domains are indicated by arrows. Bars indicate codons mapped to resistance to ganciclovir (GCV), cidofovir (CDV), and foscarnet (PFA). Regions showing variation in drug-sensitive isolates (Var) are indicated by shaded boxes. APB, accessory protein binding.