IDENTIFICATION OF MULTIDRUG RESISTANT HIV1 ISOLATES

最近的研究表明，有效的、合理设计的药物组合即使不能完全阻止HIV-1的复制，也可以大大减少。然而，对于先前接受过抗逆转录病毒治疗的患者，联合治疗的益处大大减少。虽然有13种抗逆转录病毒药物可用，但每一类抑制剂都存在相当大的交叉耐药性。初步数据表明，目前的一些耐药HIV-1分离株已经对临床开发中的许多药物产生交叉耐药。本研究计划确定接受大多数可用的RT和蛋白酶抑制剂治疗的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)已发表的HIV-1 RT和蛋白酶序列，（II） ACTG试验中获得的RT和蛋白酶序列，以及（III）在旧金山湾区bb0 500名HIV-1感染患者的临床管理中获得的RT和蛋白酶序列。将从这些分离株中创建感染性生物克隆和重组分子克隆；将评估他们对现有和实验性抗逆转录病毒药物的易感性；此外，还将评估特异性多药耐药突变在定点诱变和病毒传代实验中的作用。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。对于抗逆转录病毒药物开发和耐药性领域的研究人员来说，一组具有良好特征的多药耐药HIV-1分离株也将具有最大价值。

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.