: This application is for the competitive renewal of ROl A143847 entitled """"""""Structure/function relationships in HIV-1 co-receptors."""""""" Gp120 binding to the CD4 receptor drives reordering of the gpl2O core structure and creates/exposes a co-receptor binding site on gpl2O. CCR5 and CXCR4 are the most biologically relevant HIV-1 co-receptors. Over the past two and a half years, grant A143847 has supported a number of studies that enabled my laboratory to map the determinants of CCR5 and CXCR4 co-receptor function. We demonstrated that negatively charged residues and sulfotyrosines in the CCR5 amino-terminal domain (Nt) interact directly with gpl2O and are indispensable for HIV-1 fusion and entry. We also demonstrated that CXCR4 co-receptor function depends on similar residues in the Nt and second extracellular loop. Our studies with inhibitors of CCR5 co-receptor function showed that regions not directly involved in gpl20 binding also play an important role in viral entry. These findings successfully address the original specific aims and lay the groundwork for advanced studies of co-receptor structure/function relationships. Our continuing goal is to define how HIV-1 envelope glycoproteins interact with fusion co-receptors. To this end, we will elucidate the role of sulfotyrosines in CCR5- and CXCR4-mediated fusion and entry, study co-receptor interactions with envelope glycoproteins from non-clade B isolates, and characterize novel lead compounds that inhibit viral entry by interfering with CCR5 or CXCR4 co-receptor function. Our work will provide a detailed molecular picture of the protein complex that mediates HIV-1 membrane fusion and viral entry, and will advance the development of more potent and specific inhibitors that are clinically relevant.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI043847-05
Application #
6352097
Study Section
Special Emphasis Panel (ZRG1-AARR-1 (01))
Program Officer
Wassef, Nabila M
Project Start
1998-06-15
Project End
2006-05-31
Budget Start
2001-06-01
Budget End
2002-05-31
Support Year
5
Fiscal Year
2001
Total Cost
$401,875
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461
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Cormier, E G; Tran, D N; Yukhayeva, L et al. (2001) Mapping the determinants of the CCR5 amino-terminal sulfopeptide interaction with soluble human immunodeficiency virus type 1 gp120-CD4 complexes. J Virol 75:5541-9
Nagashima, K A; Thompson, D A; Rosenfield, S I et al. (2001) Human immunodeficiency virus type 1 entry inhibitors PRO 542 and T-20 are potently synergistic in blocking virus-cell and cell-cell fusion. J Infect Dis 183:1121-5
Dragic, T; Trkola, A; Thompson, D A et al. (2000) A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc Natl Acad Sci U S A 97:5639-44
Cormier, E G; Persuh, M; Thompson, D A et al. (2000) Specific interaction of CCR5 amino-terminal domain peptides containing sulfotyrosines with HIV-1 envelope glycoprotein gp120. Proc Natl Acad Sci U S A 97:5762-7

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