The replication of the human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2) can be markedly suppressed in many patients, but the current therapies have not eradicated infection. Thus, an understanding of how HIV interacts with T cells and monocytes in cellular reservoirs is of biological and clinical importance. HIV-2 causes AIDS, but generally after a much longer asymptomatic period than follows infection with HIV-1. Therefore, an understanding of the biological differences and similarities between HIV-2 and HIV-1 is of clinical importance. To understand the viral and host factors which affect disease progression, our laboratory has analyzed the interaction between cellular factors and the HIV-2 transcriptional promoter. We have identified five cis-acting HIV-2 enhancer elements which respond specifically to cellular stimulation and have focused on the peri-ets (pets) site, not found in HIV-1, which we have shown to be important to the replication of HIV-2 in cell lines and which binds at least two important cellular proteins in vitro: GLI-2/THP, a member of the GLI protooncogene family and DEK, previously associated with leukemia and juvenile rheumatoid arthritis, which we have shown to be a site-specific DNA-binding protein which mediates signal transduction through the pets site. DEK has little similarity to other known proteins and thus would appear to be a novel type of DNA binding protein. GLI-2/THP, while binding to the pets site in vitro, activates HIV-2 and HIV-1 gene expression through a pets- independent mechanism and synergizes with both Tat-1 and Tat-2. We now propose to further study the role of the pets site, GLI-2/THP and DEK in regulating HIV-2 (and HIV-1) transcription and replication. The mechanism of action and the biological importance of the GLI-2/THP-Tat interaction and the regulatory pathway by which DEK modulates HIV-2 gene expression will be examined. Further studies will address the role of the pets site and adjacent enhancer elements in HIV-2 replication in specific cell types. Also, an HIV-2 infectious clone in which the pets site has been mutated will be used to look for other genetic mutations which compensate for the mutated pets site and affect replication. These studies should cast light on how cellular proteins contribute to the regulation of HIV-2 and HIV-1 transcription and replication and suggest novel therapeutic interventions for both viruses.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI036685-09
Application #
6510557
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Program Officer
Young, Janet M
Project Start
1994-09-01
Project End
2003-06-30
Budget Start
2002-07-01
Budget End
2003-06-30
Support Year
9
Fiscal Year
2002
Total Cost
$318,986
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
791277940
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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Faulkner, Neil E; Lane, Brian R; Bock, Paul J et al. (2003) Protein phosphatase 2A enhances activation of human immunodeficiency virus type 1 by phorbol myristate acetate. J Virol 77:2276-81
Lane, Brian R; King, Steven R; Bock, Paul J et al. (2003) The C-X-C chemokine IP-10 stimulates HIV-1 replication. Virology 307:122-34
Sitwala, Kajal V; Mor-Vaknin, Nirit; Markovitz, David M (2003) Minireview: DEK and gene regulation, oncogenesis and AIDS. Anticancer Res 23:2155-8
Hayes, Michael M; Lane, Brian R; King, Steven R et al. (2002) Prostaglandin E(2) inhibits replication of HIV-1 in macrophages through activation of protein kinase A. Cell Immunol 215:61-71
Lane, Brian R; Liu, Jianguo; Bock, Paul J et al. (2002) Interleukin-8 and growth-regulated oncogene alpha mediate angiogenesis in Kaposi's sarcoma. J Virol 76:11570-83
Sitwala, Kajal V; Adams, Kristine; Markovitz, David M (2002) YY1 and NF-Y binding sites regulate the transcriptional activity of the dek and dek-can promoter. Oncogene 21:8862-70
Hayes, Michael M; Lane, Brian R; King, Steven R et al. (2002) Peroxisome proliferator-activated receptor gamma agonists inhibit HIV-1 replication in macrophages by transcriptional and post-transcriptional effects. J Biol Chem 277:16913-9
Faulkner, N E; Hilfinger, J M; Markovitz, D M (2001) Protein phosphatase 2A activates the HIV-2 promoter through enhancer elements that include the pets site. J Biol Chem 276:25804-12
Smith, M J; Gitlin, S D; Browning, C M et al. (2001) GLI-2 modulates retroviral gene expression. J Virol 75:2301-13

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