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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
First Independent Research Support & Transition (FIRST) Awards (R29)
Project #
5R29AI035483-04
Application #
2004067
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Project Start
1993-12-01
Project End
1998-11-30
Budget Start
1996-12-01
Budget End
1997-11-30
Support Year
4
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218