Human herpesvirus-6 (HHV-6) is a recently isolated herpesvirus which is prevalent in the human population and has been identified as the cause of exanthem subitem, a mild febrile disease of infants. HHV-6 has been isolated from the peripheral blood lymphocytes of patients with AIDS and lymphoproliferative disorders and undergoes productive infections of predominantly in activated CD4+ T-lymphocytes both in vivo and in vitro. Thus, the tropism of HHV-6 in T-lymphocytes is the same as HIV-1, ad indeed these viruses have been shown to coinfect the same cells in vitro, leading to accelerated HIV-1 gene expression and cell death. These and other studies, including the ability of HHV-6 to induce CD4 expression in CD4-CD8+ T-cells, thus expanding the host cell range of HIV-1, has led to speculation that HHV- may act as a cofactor in the progression of asymptomatic HIV-infection to AIDS in dually infected individuals. Ultrastructural and DNA sequencing studies of the HHV-6 genome have demonstrated that it comprises a 140kbp unique component flanked by single direct repeat units of 10kbp at each terminus, is likely to have a coding capacity for approximately 100 genes, and that the genetic content and organization of HHV-6 resembles that of human cytomegalovirus (HCMV). Of particular importance with respect to HHV-6 genes that may control homologous and heterologous gene expression are those located within the pressed putative major immediate-early (MIE) locus of the genome, which include a homologue of the HCMV UL122 (IE2) gene. The MIE genes of the other B-herpesvirus have been shown to encode transcriptional regulatory proteins which function to control viral lytic cycle gene expression. Our principal aims are: (1) to identify and map HHV-6 IE transcripts to the viral genome, thus identifying HHV-6 IE transcription units and confirming the kinetic class of the putative IE genes that we have already identified and sequenced, and (2) to structurally and functionally characterize the gene products encoded by the putative MIE locus, at least one of which we have already shown to function as an activator of HIV-1 LTR-directed transcription. Our work will include the use of transient transfection assays to identify HHV-6 MIE regulatory genes, characterization of MIE mRNAs and encoded proteins via cDNA cloning and sequencing, and detailed mutational analysis of the HHV-6 equivalent of the beta-herpesvirus-conserved IE2-type MIE gene product. These studies of HHV-6 MIE genes will define regulatory mechanisms of importance in potential in vivo interactions between HHV-6 and HIV.
| Nicholas, J (1996) Determination and analysis of the complete nucleotide sequence of human herpesvirus. J Virol 70:5975-89 |
