Currently approved drugs inhibit HIV-1 replication by interfering with the enzymatic activities of either protease (PR) or reverse transcriptase (RT). The ability of HIV to rapidly evolve drug resistance, together with the toxicity problems of current antiretroviral regimens, requires the development of additional classes of antiviral drugs. As an essential enzyme for HIV-1 replication, Integrase (IN) is an attractive antiviral target. Recent technological advances have resulted in the identification of good lead compounds that could serve as the starting point for structure-based Integrase Inhibitor (INI) design. Clinical evaluation of some of these compounds is underway. The overall goal of this project is to develop rapid, sensitive phenotypic and genotypic assays to evaluate the susceptibility of HIV-1 isolates to inhibitors of all HIV-1 viral enzymes, with particular emphasis on INIs. We will construct two alternative vector systems that produce virus particles containing HIV-1 pol proteins derived from patient isolates. These assays will be based on the technology underlying PhenoSense HIVTM, an existing cell-based antiviral drug susceptibility assay that evaluates PR and RT inhibitors. At the completion of Phase I, we will be able to provide Research Use Only (RUO) assays to pharmaceutical companies developing inhibitors of any pol enzymatic function. In addition to aiding in the discovery and development of first generation INIs by characterizing resistance in vitro, the RUO assays will assist in the discovery and development of second-generation drugs that are active against drug resistant strains by screening new drug candidates against a library of resistance test vectors. Additionally, the RUO assays will allow monitoring the development of IN inhibitor resistant HIV-1 during the clinical evaluation of investigational agents. Characterizing the performance of these RUO assays during Phase I will facilitate their clinical validation as Phase II of the project. For the selection of potent antiretroviral treatment regimens that include combinations of active PR, RT and IN inhibitors.
| Hatano, Hiroyu; Lampiris, Harry; Fransen, Signe et al. (2010) Evolution of integrase resistance during failure of integrase inhibitor-based antiretroviral therapy. J Acquir Immune Defic Syndr 54:389-93 |
