Human immunodeficiency virus (HIV) is the etiological agent for AIDS and individuals infected with HIV usually go through a prolonged latent period without developing any clinical disease. The factors contributing to the termination of latency are not well understood and it is believed that infection with other viruses may play an important role by providing the activation signals to terminate the HIV latency. Among the viruses that have been studied, the newly identified human herpesvirus-6 (HHV-6) has been implicated as an important viral cofactor. HHV-6 is isolated frequently from patients with AIDS and more importantly, HHV-6 infects the same cell type as HIV, namely, CD4+ T cells and monocytes, both in vivo and in vitro. Our long term objectives are to understand the biology of HIV and HHV-6 interactions, the role played by HHV-6 in enhancing the pathogenesis of HIV Infection and vice versa. Our studies show that the promoter in the long terminal repeats (LTR) of HIV-1 can be transactivated by infection of T cells with HHV-6 and four transactivating gene fragments of group A HHV-6(GS) (pZVB70, pZVH14, pZVB10 and pGD41) have been identified. The highest level of transactivation was seen with the 22kb pZVB70 DNA clone and we have identified a 143 amino acids ORF (B7O1) within the pZVB70 DNA clone and a nuclear phosphoprotein P41 encoded within the pGD41 clone as the transactivating proteins. The NF-kB binding sites in the HIV-LTR appear to be important for the transactivation mediated by these two proteins, and the B701 protein but not the P41 protein can induce TNF-alpha in monocytes. Preliminary studies also show that HIV-1 expression can activate group A HHV-6(GS) viral expression in T cells. Our goals for the next funding period are: (1) to define the mechanism by which the two HHV- 6 gene products, B701 and P41, transactivate the HIV LTR dependent gene expression; (2) to determine the domains of the B701 and P41 essential for transactivation, and to identify and characterize the native proteins in HHV-6 infected cells; (3) to identify and characterize other group A HHV- 6(GS) gene products with transactivating function, and to define the mechanism of transactivation; (4) to identify the specific HIV gene(s) involved in the induction of HHV-6 gene expression. The studies proposed here are significant as they will generate important information about how HHV-6 can act as a co-factor, the gene products involved and their mechanism of actions, which will eventually lead to design ways to block such interactions.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI030356-09
Application #
2409884
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Project Start
1993-07-01
Project End
1999-01-31
Budget Start
1997-02-01
Budget End
1999-01-31
Support Year
9
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Nebraska Lincoln
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
555456995
City
Lincoln
State
NE
Country
United States
Zip Code
68588
Wen, Hui-Ju; Minhas, Veenu; Wood, Charles (2009) Identification and characterization of a new Kaposi's sarcoma-associated herpesvirus replication and transcription activator (RTA)-responsive element involved in RTA-mediated transactivation. J Gen Virol 90:944-53
Flebbe-Rehwaldt, L M; Wood, C; Chandran, B (2000) Characterization of transcripts expressed from human herpesvirus 6A strain GS immediate-early region B U16-U17 open reading frames. J Virol 74:11040-54
Chan, S R; Bloomer, C; Chandran, B (1998) Identification and characterization of human herpesvirus-8 lytic cycle-associated ORF 59 protein and the encoding cDNA by monoclonal antibody. Virology 240:118-26
Chandran, B; Bloomer, C; Chan, S R et al. (1998) Human herpesvirus-8 ORF K8.1 gene encodes immunogenic glycoproteins generated by spliced transcripts. Virology 249:140-9
McCarthy, M; He, J; Wood, C (1998) HIV-1 strain-associated variability in infection of primary neuroglia. J Neurovirol 4:80-9
He, J; Bhat, G; Kankasa, C et al. (1998) Seroprevalence of human herpesvirus 8 among Zambian women of childbearing age without Kaposi's sarcoma (KS) and mother-child pairs with KS. J Infect Dis 178:1787-90
McCarthy, M; Auger, D; He, J et al. (1998) Cytomegalovirus and human herpesvirus-6 trans-activate the HIV-1 long terminal repeat via multiple response regions in human fetal astrocytes. J Neurovirol 4:495-511
Zhou, Y; Chandran, B; Wood, C (1997) Transcriptional patterns of the pCD41 (U27) locus of human herpesvirus 6. J Virol 71:3420-30
Harrington Jr, W; Sieczkowski, L; Sosa, C et al. (1997) Activation of HHV-8 by HIV-1 tat. Lancet 349:774-5
Hutto, C; Zhou, Y; He, J et al. (1996) Longitudinal studies of viral sequence, viral phenotype, and immunologic parameters of human immunodeficiency virus type 1 infection in perinatally infected twins with discordant disease courses. J Virol 70:3589-98

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