IDENTIFICATION OF MULTIDRUG RESISTANT HIV1 ISOLATES

描述：(摘自申请人的摘要)最近的研究表明，如果不能完全阻止HIV-1的复制，那么通过有效的、合理设计的药物组合，可以显著减少HIV-1的复制。然而，在以前接受过抗逆转录病毒治疗的患者中，联合治疗的好处大大减少。虽然有13种抗逆转录病毒药物可用，但每类抑制剂都存在相当大的交叉耐药性。初步数据表明，目前一些耐药的HIV-1分离株已经对临床开发中的许多药物产生交叉耐药性。这项建议计划从接受大多数可用逆转录酶和蛋白酶抑制剂治疗的患者中确定HIV-1分离株中RT和蛋白酶突变的模式。该应用程序将分析(I)公布的HIV-1RT和蛋白酶序列，(Ii)在ACTG试验中获得的RT和蛋白酶序列，以及(Iii)在旧金山湾区对500名HIV-1感染者进行临床治疗期间获得的RT和蛋白酶序列。将从这些分离株中创建具有感染性的生物学和重组分子克隆；将评估它们对现有的和实验性的抗逆转录病毒药物的敏感性；并将评估特定的多药耐药突变在定点突变和病毒传递实验中的作用。了解导致多药耐药的基因变化对于开发新的抗逆转录病毒药物、设计最佳药物组合以及对个别患者的临床管理至关重要。对抗逆转录病毒药物开发和耐药性领域的研究人员来说，一套具有良好特性的多重耐药HIV-1分离株也将具有最大的价值。

DESCRIPTION: (Adapted from Applicant's Abstract) Recent studies show that HIV-1 replication can be dramatically curtailed, if not completely arrested, with potent, rationally-designed drug combinations. The benefits of combination therapy, however, are greatly diminished in patients who have received previous antiretroviral therapy. Although 13 antiretroviral drugs are available, there is considerable cross-resistance within each class of inhibitors. Preliminary data suggest that some of the current drug-resistant HIV-1 isolates are already cross-resistant to many of the drugs in clinical development. This proposal plans to identify patterns of RT and protease mutations developing in HIV-1 isolates from patients receiving treatment with the majority of available RT and protease inhibitors. This application will analyze (I) published HIV-1 RT and protease sequences, (II) RT and protease sequences obtained in ACTG trials, and (III) RT and protease sequences obtained during the clinical management of >500 HIV-1-infected patients in the San Francisco Bay area. Infectious biological and recombinant molecular clones will be created from these isolates; their susceptibility to available and experimental antiretroviral drugs will be assessed; and, the role of specific multidrug-resistance mutations in site-directed mutagenesis and virus passage experiments will be assessed. An understanding of the genetic changes responsible for multidrug-resistance is essential for the development of new antiretroviral drugs, for designing optimal drug combinations, and for the clinical management of individual patients. A set of well-characterized multidrug-resistance HIV-1 isolates will also be of the utmost value to researchers in the areas of antiretroviral drug development and drug resistance.