Molecular biology of human herpesviruses 6A and 6B

Human herpesvirus 6 variant A (HHV-6A) and human herpesvirus 6 variant B (HHV-6B) are closely related herpesviruses. No disease has been specifically associated with HHV-6A, whereas HHV-6B is the major etiologic agent of exanthem subitum. Both viruses may be opportunistic pathogens in the immunocompromised patient. HHV-6 genomes have low G+C contents for herpesviruses (43%); they consist of a 141-kb unique segment that is flanked by single copies of a directly repeated sequence that can vary from 10 to 13 kb. HHV-6A and HHV-6B encode homologs of many conserved herpesvirus proteins and are classified as beta-herpesviruses based on their close genetic relationship with human cytomegalovirus. HHV-6A and HHV-6B are even more closely related to the recently discovered human herpesvirus 7. HHV-6 encodes homologs of the seven genes that are essential for origin-dependent herpes simplex virus type 1 DNA replication, including the origin-binding protein, which has no clear homolog in human cytomegalovirus. The HHV-6B origin-binding protein binds to sequences with similarities to alpha-herpesvirus replication origins that lie within a genomic segment that can serve as a replication origin in transient replication assays. Both HHV-6 variants encode homologs of the adeno-associated virus type 2 Rep protein; the role of this protein during infection is unknown. HHV-6 induces synthesis of a broad range of host cell proteins, including interferon alpha, CD4, interleukin-1 beta, and tumor necrosis factor alpha, and also induces expression of the human immunodeficiency virus type 1 LTR promoter. Little is known about the process by which HHV-6 regulates gene expression.