Human immunodeficiency viruses (HIV-1 and HIV-2) and simian immunodeficiency viruses (SIV) infect CD-4 positive lymphocytes and monoccytes in their respective hosts. the entry of these viruses into target lymphocytes and the eventual destruction of the infected cells are mediated by the viral envelope glycoproteins. HIV-1 entry involves binding of the viral gp120 exterior envelope glycoprotein and CD4, the primary receptor on the target cell. recently, it has been shown that gp120-CD4 interaction creates a high affinity binding site for specific chemokine receptors, which act as second receptors for HIV-1. Laboratory-adapted and T cell line-tropic HIV-1 isolates use the alpha-chemokine, CXCR4, while macrophage-tropic viruses use the beta-chemokine receptor, CCR5, to mediate entry. Binding of the gp120-CD4 complex to CXCR4 or CCR5 presumably triggers subsequent conformational changes in the envelope glycoproteins leading to fusion of the viral target cell membranes.
the specific aims of this proposal are: 1) To define the regions on the HIV-1 gp120 envelope glycoprotein that interact with CCR5 and CXCR4. 2) To define regions on the CD4 glycoprotein that interact with chemokine receptors and to assess the biological significance of this interaction. 3) To define regions on the CCR5 and CXCR4 chemokine receptors important for HIV-1 entry and for the natural function of these receptors.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041851-03
Application #
2887560
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Program Officer
Plaeger, Susan F
Project Start
1997-09-01
Project End
2002-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
149617367
City
Boston
State
MA
Country
United States
Zip Code
02215
Madani, Navid; Hubicki, Amy M; Perdigoto, Ana Luisa et al. (2007) Inhibition of human immunodeficiency virus envelope glycoprotein- mediated single cell lysis by low-molecular-weight antagonists of viral entry. J Virol 81:532-8
Schon, Arne; Madani, Navid; Klein, Jeffrey C et al. (2006) Thermodynamics of binding of a low-molecular-weight CD4 mimetic to HIV-1 gp120. Biochemistry 45:10973-80
Wang, Jianbin; Babcock, Gregory J; Choe, Hyeryun et al. (2004) N-linked glycosylation in the CXCR4 N-terminus inhibits binding to HIV-1 envelope glycoproteins. Virology 324:140-50
Cavacini, Lisa; Duval, Mark; Song, Leslie et al. (2003) Conformational changes in env oligomer induced by an antibody dependent on the V3 loop base. AIDS 17:685-9
Xiang, Shi-Hua; Wang, Liping; Abreu, Mariam et al. (2003) Epitope mapping and characterization of a novel CD4-induced human monoclonal antibody capable of neutralizing primary HIV-1 strains. Virology 315:124-34
Yang, Xinzhen; Mahony, Erin; Holm, Geoff H et al. (2003) Role of the gp120 inner domain beta-sandwich in the interaction between the human immunodeficiency virus envelope glycoprotein subunits. Virology 313:117-25
Raja, Aarti; Venturi, Miro; Kwong, Peter et al. (2003) CD4 binding site antibodies inhibit human immunodeficiency virus gp120 envelope glycoprotein interaction with CCR5. J Virol 77:713-8
Labrijn, Aran F; Poignard, Pascal; Raja, Aarti et al. (2003) Access of antibody molecules to the conserved coreceptor binding site on glycoprotein gp120 is sterically restricted on primary human immunodeficiency virus type 1. J Virol 77:10557-65
Babcock, Gregory J; Farzan, Michael; Sodroski, Joseph (2003) Ligand-independent dimerization of CXCR4, a principal HIV-1 coreceptor. J Biol Chem 278:3378-85
Gao, Jinming; Choe, Hyeryun; Bota, Dalena et al. (2003) Sulfation of tyrosine 174 in the human C3a receptor is essential for binding of C3a anaphylatoxin. J Biol Chem 278:37902-8

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