NUCLEOTIDE-SEQUENCE ANALYSIS OF A 38.5-KILOBASE-PAIR REGION OF THE GENOME OF HUMAN HERPESVIRUS-6 ENCODING HUMAN CYTOMEGALOVIRUS IMMEDIATE-EARLY GENE HOMOLOGS AND TRANSACTIVATING FUNCTIONS

Human herpesvirus 6 (HHV-6) is prevalent in the human population, with primary infection occurring early in life. Its predominant CD4(+) T-l ymphocyte tropism, its ability to activate human immunodeficiency viru s type 1 (HIV-1) gene expression in vitro, and its upregulation of CD4 expression has led to speculation that HHV-6 may act as a positive co factor in the progression of HIV infection to AIDS in individuals infe cted with both viruses. Previous sequencing studies of restricted regi ons of the 161.5-kbp genome of HHV-6 have demonstrated unequivocally t hat it is a member of the betaherpesvirus subgroup and have indicated that the HHV-6 genome is generally collinear with the unique long (U-L ) component of human cytomegalovirus (HCMV). In the work described in this report we have extended these sequencing studies by determining t he primary structure of 38.5-kbp of the HHV-6 genome (genomic position 21.0 to 59.5 kbp). Within the sequenced region lie 31 open reading fr ames, 20 of which are homologous to positional counterparts in HCMV. O f particular significance is the identification of homologs of the HCM V UL36-38 and US22-type genes, which have been shown to encode transac tivating proteins. We show that DNA sequences encoding these HHV-6 hom ologs were able to transactivate HIV-1 long terminal repeat-directed c hloramphenicol acetyltransferase expression in cotransfection assays, thus demonstrating functional as well as structural conservation of th ese betaherpesvirus-specific gene products. Our data therefore confirm the close relationship between HHV-6 and HCMV and identify putative i mmediate-early regulatory genes of HHV-6 likely to play key roles in l ytic replication and possibly also in the interactions between HHV-6 a nd HIV in dually infected cells.