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Constitutive cell surface association between CD4 and CCR5
1Laboratory of Experimental and Computational Biology, National Cancer Institute-Frederick Cancer Research and Development Center, National Institutes of Health, Miller Drive, Frederick, MD 21702-1201, USA.
Summary
The human immunodeficiency virus type 1 (HIV-1) receptor CD4 directly binds to the coreceptor CCR5 before viral entry. This interaction, independent of viral proteins, suggests new therapeutic targets for HIV-1 infection and vaccine development.
Area of Science:
- Virology
- Immunology
- Cell Biology
Background:
- Human immunodeficiency virus type 1 (HIV-1) entry requires interaction between the viral envelope glycoprotein (Env), CD4 receptor, and a coreceptor, typically CCR5.
- Understanding the initial molecular interactions is crucial for developing effective antiviral strategies.
Purpose of the Study:
- To investigate the direct association between CD4 and coreceptors in the absence of viral ligands.
- To explore the potential role of this interaction in HIV-1 entry and pathogenesis.
Main Methods:
- Coimmunoprecipitation assays were used to detect the association between CD4 and CCR5/CXCR4.
- Antibody inhibition assays were performed to assess the functional relevance of the CD4-CCR5 interaction.
Main Results:
- CD4 specifically associates with CCR5 constitutively, independent of HIV-1 gp120.
- This CD4-CCR5 interaction is significantly stronger than CD4-CXCR4 association and is not enhanced by gp120.
- Antibodies targeting CD4 or CCR5 inhibited this interaction and HIV-1 infection.
Conclusions:
- A direct, constitutive interaction exists between CD4 and CCR5, likely mediated by specific domains of each protein.
- This interaction may play a role in HIV-1 entry and pathogenesis, offering potential new targets for antiretroviral drugs and vaccine development.
- The constitutive association of G protein-coupled receptors highlights novel possibilities for receptor cross-talk.