Grant: Operating Grant: Industry-partnered Collaborative Research - Rx&D partner

The life-long nature of HAART and the ability of HIV to mutate rapidly have led to concerns about the determinants of treatment response and toxicity, as well as the development of drug resistance. It is important to develop novel classes of antiretroviral agents as well as to improve the accessibility to those agents for patients resistant to current regimens. Recently Health Canada approved a new antiretroviral drug from a novel class called CCR5 antagonists, which has offered new hope to patients who have become resistant to traditional HIV antiretroviral drugs. This new drug inhibits HIV-1 binding to one of its co-receptors, CCR5, thereby preventing viral entry into target cells. In order for CCR5 antagonists to be useful for patients, it must first be determined what type of co-receptor their virus uses (tropism). Currently, patients must be screened using a Phenotypic Assay (Trofile) which takes weeks to produce results and costs approximately $2000 per sample. We propose to develop a sequencing-based clinical assay that will have a direct positive impact on patients by reducing delays and expense for co-receptor tropism determination. We will use novel methods of analyzing genetic sequence data, as well as new ¿deep sequencing¿ technology, to predict HIV co-receptor tropism, with an expected 10-fold decrease in cost. We will also develop our own phenotypic assay to assist in the validation of our sequencing-based approach. With our proposed project, we can combine basic science and clinical information to provide a more efficient and more cost-effective screening assay. In addition, this proposal should also lead to significant improvements in monitoring HIV. The equipment purchased (primarily a Roche/454 Genome Sequencer FLX) will allow our laboratory to develop more sensitive HIV drug resistance assays for existing anti-HIV agents, as well as assays for the eventual resistance to the CCR5 antagonists.