Two distinct CCR5 domains can mediate coreceptor usage by human immunodeficiency virus type 1

Area of Science:

• Virology
• Immunology
• Structural Biology

Background:

• CCR5 is the primary fusion coreceptor for macrophage-tropic HIV-1 strains.
• Understanding CCR5's structure is vital for defining HIV-1 entry mechanisms.

Purpose of the Study:

• To delineate the structural components of CCR5 essential for HIV-1 envelope (Env)-mediated membrane fusion.
• To investigate the role of CCR5 in HIV-1 coreceptor usage and evolution.

Main Methods:

• Analysis of CCR5 homologs, chimeras, and mutants using a gene reporter cell-cell fusion assay.
• Site-directed mutagenesis to identify critical residues and functional regions.
• Development of a novel monoclonal antibody against CCR5.

Main Results:

• Simian CCR5 homologs, but not murine, effectively served as HIV-1 fusion coreceptors.
• Distinct functional regions within CCR5, including the N-terminal domain and extracellular loops, were identified for Env-mediated fusion.
• Specific residues (Asp-11, Lys-197, Asp-276) were found to be critical for coreceptor function.
• CCR5's coreceptor function for HIV-1 fusion is independent of its G-protein-mediated signaling pathway.

Conclusions:

• The N-terminal domain and extracellular loops of CCR5 are key structural determinants for HIV-1 fusion.
• Specific amino acid residues significantly contribute to CCR5's role as an HIV-1 coreceptor.
• CCR5's fusion and signaling functions are separable, offering distinct avenues for therapeutic intervention.
• A new CCR5 antibody facilitates future research on receptor expression and function.