Acquired Immunodeficiency Syndrome (AIDS) is a severe disease caused by a human retrovirus, Human Immunodeficiency Virus (HIV). It is generally believed that all HIV infected individuals will eventually develop AIDS. However, the time frame from initial infection to the development of clinical AIDS is extremely variable. Some infected individuals develop the disease within months of infection while in some may take years. It is likely that the virus exists for prolonged periods in a latent form in infected individuals. It has been postulated that various factors may be involved in triggering the virus into an active state of replication and thus causing the disease. These factors include antigenic stimulation or superinfection by other viruses. Recently, a new human herpes virus-6 (HHV-6) was isolated from AIDS patients, patients with lymphoproliferative disorders and infants with roseola. Since HHV-6 also infects in vitro the same human target cells as HIV and produces a productive infection, it will be essential to study the role played by HHV-6 infection and replication in HIV-pathogenesis. We have recently demonstrated that HHV-6 can transactivate HIV-1 LTR in human T cell lines. Our preliminary studies show that HHV-6 can also transactivate HIV LTR in T lymphoblasts from norman human peripheral blood. In addition, HHV-6 and HIV-1 have been shown to productively co-infect individual human CD4+ T lymphocytes, resulting in accelerated HIV-1 expression and cellular death. It could be hypothesized that activation of latent HIV-1 by HHV-6 or vice versa, may generate a vicious cycle resulting in the depletion of CD4+ cells. HHV-6 may also play a role in the pathogenesis of AIDS by acting through CD4+ cytolysis or modulation or by chronic antigenic stimulation leading to suppression of the T cell regulatory mechanisms and may lead to tumor development and progression. Our overall objective of this proposed project is to understand how HHV-6 acts as a co-factor in HIV activation, its mechanisms involved and its significance in activating latent HIV infection. Our approach is to first identify the HHV-6 gene(s) that is involved in HIV activation. We are also proposing to see if HIV itself can activate HHV-6 replication, since in vitro, HHV-6 infection alone is cytolytic for T cells. Enhancement of HHV-6 production by HIV in AIDS may also be an important factor in T cell depletion in AIDS patients. Several HHV-6 isolates with varying in vitro tropism have been identified and we will examine the ability of HHV-6 isolates with diverse tropism to activate HIV promoter and HIV in T cell lines and primary T blast cells. The studies proposed here are significant as they will generate valuable information in understanding how HHV-6 can act as co-factor in AIDS, mechanisms involved and especially its role in converting latent HIV infection.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI030356-01A1
Application #
3145326
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Project Start
1991-01-01
Project End
1993-12-31
Budget Start
1991-01-01
Budget End
1991-12-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
University of Miami Coral Gables
Department
Type
Schools of Arts and Sciences
DUNS #
City
Coral Gables
State
FL
Country
United States
Zip Code
33146
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

Showing the most recent 10 out of 20 publications