The HIV-1 Tat protein is essential for viral replication. The ability of Tat to activate RNA polymerase II elongation of the integrated provirus is mediated by a protein kinase known as P-TEFb. P-TEFb is composed of cyclin T1, a regulatory subunit and Cdk9, the catalytic subunit. Tat makes direct protein-protein contact with cyclin T1. Recent studies have shown that cyclin T1 and therefore Tat function are regulated by mechanisms that appear to be unique to primary macrophages, a cell type that is critical to HIV-1 replication and pathogenesis. Cyclin T1 protein is induced early during the normal course of macrophage differentiation, but is shut off at late times of differentiation by proteasome-mediated proteolysis. Activation of macrophages by pathogen-associated molecular patterns (PAMPs) re-induces cyclin T1, indicating that the induction of cyclin T1 is a component of an innate immune response in macrophages. HIV-1 infection of macrophages induces cyclin T1 expression, and a viral gene product(s) appears to be involved in this induction. This grant application proposes to investigate a number of hypotheses concerning molecular mechanism that regulate cyclin T1 expression in primary macrophages. Regulation of cyclin T1 and Tat function in HIV-1-infected cells will be investigated. Regulation of induction and repression of cyclin T1 in uninfected macrophages will also be investigated. The goal of the research described in this application is to provide new mechanistic information about the regulation of cyclin T1 expression in macrophages, and how such regulation impacts upon HIV-1 replication. Completion of the proposed studies will provide new knowledge about HIV-1 replication in this important cell type and may suggest strategies for therapeutic intervention. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI045374-05A2
Application #
6891759
Study Section
Special Emphasis Panel (ZRG1-AARR-D (02))
Program Officer
Sharma, Opendra K
Project Start
1999-02-15
Project End
2009-01-31
Budget Start
2005-02-01
Budget End
2006-01-31
Support Year
5
Fiscal Year
2005
Total Cost
$337,500
Indirect Cost
Name
Baylor College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030