NOVEL ASSAYS FOR MEASURING THE INHIBITION OF VIRUS ENTRY

描述(由申请人提供)： 联合应用病毒蛋白酶(PR)和逆转录酶(RT)抑制剂治疗HIV-1感染患者，在抑制病毒复制和延长患者生存方面取得了显着成功。然而，延长这些抗逆转录病毒(ARV)药物的使用通常与出现往往危及治疗的耐药病毒有关。表型和基因耐药试验的发展极大地方便了有经验的ARV治疗患者的临床管理。耐药病毒的流行和传播增加，包括对PR和RT抑制剂表现出广泛交叉耐药性的菌株，因此有必要开发新的治疗方法来对抗这种高度适应的病毒。HIV进入的抑制剂代表着一类很有前途的新型抗逆转录病毒药物。表型和基因分型检测耐药菌株的发展无疑将加速进入抑制剂的发展，提高其在临床上的实用性。第一阶段支持用于开发一种表型分析方法，用于测量HIV-1对进入抑制剂的敏感性，以及一种用于检测HIV-1包膜基因耐药突变的基因类型分析方法。第二阶段支持旨在优化、扩大和验证这两种耐药性测试，以便在临床参考实验室环境中常规使用。

DESCRIPTION (provided by applicant): Treatment of HIV-1 infected patients with combinations of inhibitors of the viral protease (PR) and reverse transcriptase (RT) enzymes has been remarkably successful in suppressing viral replication and prolonging patient survival. However, extended administration of these antiretroviral (ARV) agents is commonly associated with the emergence of resistant virus that often compromises treatment. The clinical management of ARV treatment experienced patients has been greatly facilitated by the development of phenotypic and genotypic drug resistance assays. The increase in the prevalence and spread of drug-resistant virus, including strains displaying broad cross-resistance to PR and RT inhibitors has necessitated the development of new therapeutic approaches to combat this highly adaptive virus. Inhibitors of HIV entry represent a promising new class of antiretroviral agents. The development of phenotypic and genotypic assays to detect drug resistant strains will undoubtedly accelerate the development of entry inhibitors and improve their utility in the clinic. Phase I support was used to develop a phenotypic assay that measures susceptibility of HIV-1 to entry inhibitors and a genotypic assay that detects resistance mutations in the HIV-1 envelope gene. Phase II support is intended to optimize, scale and validate these two resistance tests for routine use in a clinical reference laboratory environment.