56 Preclinical Development of Chemokine Receptor Inhibitors Donald E Mosier The Scripps Res Inst, La Jolla, CA, USA

Background:  Chemokine receptors, particularly CCR5, are attractive targets for antiviral drug development because they are members of a large family of G protein-coupled receptors (GPCR) known to be sensitive to small molecule inhibitors, and because a null mutation of CCR5 (delta 32) is protective against HIV-1 transmission and confers no known disease susceptibility.

Methods:  We and others have examined the activity of N-terminal modifications of RANTES and a number of small molecule inhibitors as antiviral agents and as modulators of CCR5 conformation or surface expression.  Several of these agents have also been tested for in vivo activity in human xenograft models and in primate models of mucusal transmission.  We have also analyzed envelope mutations associated with resistance to entry inhibitors and the process of coreceptor switching from CCR5 to CXCR4.

Results:  One common finding has been that entry inhibitors show considerable variation in activity (IC50) with different HIV-1 isolates.  This variation appears to reflect the considerable flexibility in the interaction between the viral envelope trimer and the exposed domains of the chemokine receptor.  The plasticity of this binding event suggests that the efficacy of entry inhibitors may change over the course of infection, and that different virus isolates may be more or less prone to develop resistance.  Generation of resistant mutants during selection by entry inhibitors has been rare, and resistance due to coreceptor switching even more rare.  One explanation for these findings is that mutations involved in coreceptor switching decrease the entry fitness of the virus.  Two entry inhibitors have shown activity in a SHIV mucosal transmission model, suggesting that they may be useful in preventing infection as well as treating established infection.

Conclusions:  It will be important to understand the evolution of HIV envelope:coreceptor interactions to use entry inhibitors in the most productive manner.