Co-receptor antagonists as HIV-1 entry inhibitors

A new mechanistic understanding of how HIV-1 enters cells has emerged recently, and these discoveries are now being translated into novel therapeutic agents. Along with CD4, HIV-1 requires a chemokine receptor, CCR5 or CXCR4, as an entry co-receptor, and differential co-receptor selectivity is an important determinant of viral diversity and pathogenesis. CCR5 and CXCR4 blockers have been the focus of much research and are now entering clinical trials.

Several CCR5 antagonists with anti-HIV-1 activity have been developed, including small-molecule agents, monoclonal antibodies and modified chemokines. At least four small-molecule and one antibody CCR5 inhibitor are in various stages of preclinical and clinical testing. Most or all infected individuals harbor CCR5-using variants, and promising findings have been reported from very preliminary clinical studies. CXCR4 antagonists under development include small-molecule and short-peptide inhibitors. Only a subset of late-stage individuals harbor CXCR4-using strains, and early clinical studies of CXCR4 inhibition showed some evidence of suppression in certain individuals.

Chemokine receptor antagonists offer great promise as a much-needed new class of antiviral agent. They also raise questions that are unique to agents targeting these cellular receptors, including whether drug resistance will lead to variants with altered co-receptor selectivity, the tolerability of chronically blocking receptors involved in inflammation (CCR5, CXCR4) or essential in development and hematopoesis (CXCR4), and the role of co-receptor phenotyping in selecting blocking agents. In addition to HIV-1 infection, these drugs may also have utility in inflammation, cancer, stem cell transplant and other areas.