59 Resistance to HIV Chemokine Receptor Antagonists Christos J Petropoulos*1, W Huang1, J Toma1, S Fransen1, S Bonhoeffer2, and J Whitcomb1 1ViroLogic, Inc, South San Francisco, CA, USA and 2ETH Zurich, Switzerland

HIV-1 entry inhibitors represent a diverse new class of antiretroviral agents.  Virus entry is a multi-step process involving several virus envelope proteins (gp120SU, gp41TM) and host cell receptors (CD4, CCR5, CXCR4).  The cascade of protein-protein interactions and conformational changes that mediate virus entry represent novel targets that are functionally distinct from conventional enzymatic targets.  Consequently, resistance to entry inhibitors can differ significantly from that of protease and reverse transcriptase inhibitors, and may emerge via alternative mechanisms depending on the specific molecular interaction that is targeted.  Viruses with reduced susceptibility to fusion inhibitors (enfuvirtide) display log-sigmoid inhibition curves that typically reach 100% inhibition at high drug concentrations, consistent with a competitive mechanism of inhibition and escape.  Resistance to fusion inhibitors is best described by increases in the IC_50.  In contrast, viruses with reduced susceptibility to inhibitors that antagonize envelope-co-receptor interactions often exhibit incomplete inhibition even at elevated drug concentrations.  The inability to inhibit 100% of virus replication at high drug concentrations is consistent with an allosteric mechanism of inhibition and escape.  Viruses that develop resistance to co-receptor antagonists likely acquire the ability to bind and utilize receptor-inhibitor complexes.  Consequently, resistance to allosteric co-receptor inhibitors is best described by the extent of incomplete inhibition observed at high drug concentrations.