Research Project
7766971
DESCRIPTION (provided by applicant): The overall goal of this project is to develop novel, robust, high-throughput assays to evaluate the susceptibility of to inhibitors of HIV-1 Gag and protease proteins, with particular emphasis on virion assembly and maturation. These assays will be based on proven technologies underlying Monogram Bioscience's widely used PhenoSense HIVTM and GeneSeq HIVTM drug resistance tests, i.e. recombinant virus-based and nucleic acid sequencing-based assays first developed to evaluate inhibitors of HIV-1 protease and reverse transcriptase. Currently, several assembly/maturation inhibitors are undergoing evaluation in pre-clinical and clinical studies, e.g. bevirimat (Panacos), vivecon (Myriad Genetics). Consequently, reliable, high-throughput assays are needed to support the development efforts of this promising new class of antiretroviral drugs, and eventually, their use in routine clinical practice. Since their implementation in the Monogram Clinical Reference Laboratory and commercialization in 2000, the PhenoSense HIV and GeneSeq HIV assays have been used to characterize in excess of 150,000 patient samples. In addition, both assays have been used extensively to support phase III evaluations of antiretroviral drug candidates over the past eight years, both to characterize resistance to new agents and to guide the selection of optimized background regimens. In 2003, Monogram successfully adapted the PhenoSense and GeneSeq technologies to evaluate inhibitors of HIV-1 entry (e.g. enfuvirtide, maraviroc, vivcriviroc, ibalizumab, PRO-140), and this year we completed validations for two new assays to monitor resistance to integrase inhibitors (e.g. raltegravir, elvitegravir). This application describes a straightforward, tried and true strategy to develop PhenoSense and GeneSeq HIV drug resistance assay systems that are capable of evaluating inhibitors of HIV-1 Gag and protease proteins;specifically inhibitors that target virus assembly and maturation. Because these new assay systems will include the immuno- dominant Gag region, they arelikely to prove valuable to the study of cellular immune responses. Such studies may prove valuable to vaccine design and evaluation. PUBLIC HEALTH RELEVANCE: Successful completion of the funding proposal will result in the development and validation of new genotypic and phenotypic assays that will enable the characterization of viruses that are resistant to HIV-1 assembly and maturation inhibitors and will help guide antiretroviral treatment decisions for HIV-1 infected patients. The assay will also greatly advance the genotypic and phenotypic characterization of gag-specific CTL escape variants and will prove valuable to the design and development of improved HIV vaccines and immune-modulating therapies.
