icon-folder.gif   Conference Reports for NATAP  
  42nd ICAAC Meeting
San Diego, Sept 27-31, 2002
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Entry Inhibitors & New Test to Identify Co-receptor Use
  Entry inhibitors are in various stages of development. Fusion inhibitor T-20 is expected to be approved for commercial availability by Spring 2003, and agents that target CCR5, the cellular chemokine coreceptor for HIV binding, are in development. However, CCR5 antagonists may have limited value for patients whose virus preferentially uses the CXCR4 coreceptor; it would therefore be of value to be able to determine the coreceptor use of a given patient's virus. Chris Petropoulos (ICAAC abstract H-2040) from Virologic has developed a an assay to measure coreceptor use. They showed that multiple clones with differing chemokine receptor tropisms (uses) are more commonly present in clinical isolates than previously appreciated. Only 50% of patient virus samples exclusively employed CCR5, 2% used CXCR4, and 48% of samples contained either dual-tropic viruses that used both coreceptors or a mixture of R5 and X4 viruses. As the development of chemokine fusion inhibitors advances, this assay may be useful to preselect those patients more likely to respond to specific agents.
ABSTRACT: Drugs that target HIV-1 entry will complement existing protease and reverse transcriptase inhibitors. CCR5 and CXCR4 co-receptors are promising entry inhibitor targets, but the clinical consequences of this treatment strategy remain uncertain and require further investigation. Existing co-receptor tropism assays are insensitive and lack the capacity to support large clinical studies. HIV env sequences were amplified from plasma samples and inserted into an expression vector. Virions were produced by co-transfecting cells with this env expression vector and an HIV genomic vector lacking env, but containing a luciferase gene. CD4+ cell lines that express either CCR5 or CXCR4 are infected and tropism is evaluated based on luciferase activity in the presence and absence of co-receptor inhibitors. The performance of a new co-receptor tropism assay was evaluated in a cross-sectional survey of >2000 viruses. 48% of the patient viruses used the C CR5 exclusively, 2% used the CXCR4 exclusively, and 50% used both. ``Dual-tropic'' virus populations were comprised of individual viruses that use both receptors, more so than mixtures of viruses utilizing either receptor exclusively. Dual-tropic viruses varied in their ability to utilize CCR5 and CXCR4. Longitudinal analyses identified virus populations undergoing substantial changes in receptor usage. Phylogenetic analyses of env sequences are underway to define pathways for co-receptor switching as well as genetic determinants of receptor tropism and evolution. A rapid, sensitive method to assess HIV-1 co-receptor tropism was developed that has several important applications, including (a) evaluating CCR5 inhibitor candidates for their propensity to generate X4 tropic escape mutants (b) monitoring patients receiving treatment with CCR5 inhibitors for the emergence of X4 tropic strains and (c) identifying patients that harbor X4 virus to support clinical trials of CXCR4 inhibitors.