Abstract

The focus of this project is definition of the interaction between the HIV-1 envelope protein, gp120, the CD4 receptor for the virus, and the CCR5 chemokine receptor which is the predominant co-receptor for HIV-1. We hypothesize that this interaction can be disrupted by small molecules (e.g. peptidomimetics) and that such agents will be effective antiviral agents. The interaction of gp120 with CD4 has been extensively characterized, and the first two aims of the current project will characterize the interaction of gp120 with CCR5. Mutations in envelope other than the V3 loop, as well as scanning and random mutants in the V3 loop will be examined for their effects on gp120 interactions with CCR5. Infection, fusion, and binding assays will be used to characterize the CCR5-gp120 interaction. Chimeric chemokine receptors will also be examined to identify domains in CCR5 critical for gp120 interaction.
The third aim of this proposal is to target CCR5 expression to murine macrophages, together with human CD4, to determine if these cells can be infected with HIV-1, as a potential animal model for studies of HIV-1 pathogenesis and drug and vaccine development.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI024745-11A1
Application #
2542899
Study Section
AIDS and Related Research Study Section 1 (ARRA)
Program Officer
Cremer, Kenneth J
Project Start
1987-04-01
Project End
2001-12-31
Budget Start
1998-01-01
Budget End
1998-12-31
Support Year
11
Fiscal Year
1998
Total Cost
Indirect Cost

  Institution

Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130

  Publications

Hood, Joshua L; Jallouk, Andrew P; Campbell, Nancy et al. (2013) Cytolytic nanoparticles attenuate HIV-1 infectivity. Antivir Ther 18:95-103
McCulley, Anna; Ratner, Lee (2012) HIV-2 viral protein X (Vpx) ubiquitination is dispensable for ubiquitin ligase interaction and effects on macrophage infection. Virology 427:67-75
Belshan, Michael; Kimata, Jason T; Brown, Charles et al. (2012) Vpx is critical for SIVmne infection of pigtail macaques. Retrovirology 9:32
Harmon, Brooke; Campbell, Nancy; Ratner, Lee (2010) Role of Abl kinase and the Wave2 signaling complex in HIV-1 entry at a post-hemifusion step. PLoS Pathog 6:e1000956
Zhang, Menghua; Evans, Stella; Yuan, Jinyun et al. (2010) HIV-1 determinants of thrombocytopenia at the stage of CD34+ progenitor cell differentiation in vivo lie in the viral envelope gp120 V3 loop region. Virology 401:131-6
Bhatia, Ajay K; Kaushik, Rajnish; Campbell, Nancy A et al. (2009) Mutation of critical serine residues in HIV-1 matrix result in an envelope incorporation defect which can be rescued by truncation of the gp41 cytoplasmic tail. Virology 384:233-41
Salim, Aneeza; Ratner, Lee (2008) Modulation of beta-catenin and E-cadherin interaction by Vpu increases human immunodeficiency virus type 1 particle release. J Virol 82:3932-8
Harmon, Brooke; Ratner, Lee (2008) Induction of the Galpha(q) signaling cascade by the human immunodeficiency virus envelope is required for virus entry. J Virol 82:9191-205
Cheng, Xiaogang; Belshan, Michael; Ratner, Lee (2008) Hsp40 facilitates nuclear import of the human immunodeficiency virus type 2 Vpx-mediated preintegration complex. J Virol 82:1229-37
Bhatia, Ajay K; Campbell, Nancy; Panganiban, Antonito et al. (2007) Characterization of replication defects induced by mutations in the basic domain and C-terminus of HIV-1 matrix. Virology 369:47-54

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