DEVELOPMENTAL VIROLOGY

发育病毒学

• 批准号: 3791756
• 负责人: ROBERT T SCHOOLEY
• 金额: --
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3791756
• 关键词: 2'3' dideoxycytidine; 2'3' dideoxyinosine; HIV infections; antiAIDS agent; bioassay; clinical trials; cooperative study; drug screening /evaluation; genotype; human immunodeficiency virus 1; human subject; mass screening; molecular cloning; mutant; polymerase chain reaction; zidovudine

Nucleoside-based inhibitors of the essential HIV-1 enzyme reverse transcriptase (RT) prolong survival in patients with AIDS and delay disease progression in patients with earlier stages of HIV infection. Although an increasing number of HIV-1 isolates with reduced susceptibility to zidovudine (ZDV), dideoxyinosine (ddI), and dideoxycytidine (ddC) are being reported, the clinical significance of viral drug resistance is still unproven. Nevertheless, it is likely that the emergence of a pool of virus with reduced susceptibility to RT inhibitors is responsible, at least in part, for disease progression in patients treated with these drugs. Thus, testing drug susceptibility is likely to assume an increasingly important place in the design of clinical trials of antiretroviral therapy and in clinical practice. As in other infectious diseases, the use of combination chemotherapy may prevent the emergence of drug resistance and minimize toxicity. However, in vitro synergy studies reported to date have used tissue culture-adapted strains of HIV-1 that may have different biological properties as compared to clinical isolates. As participants in the ACTG Virology Resistance Working Group, we propose to develop and test a standardized protocol for testing drug-susceptibility of low-passage clinical isolates of HIV-1 from patients enrolled in ACTG trials of antiretroviral agents such as ZDV, ddI, ddC, and L-697,661. RT genes from drug-resistant isolates will be analyzed by selective PCR amplification or by cloning and sequencing to detect genotypic changes associated with drug resistance. The effect of in vitro selective pressure on the emergence of high-level drug resistance from populations of HIV-1 with intermediate drug susceptibility or mixed genotypes will be studied. Combinations of antiretroviral agents will be tested in vitro for synergy using low-passage HIV-1 isolates with reduced sensitivity to one or more drugs.

基于核苷的HIV-1逆转酶抑制剂 逆转录酶（RT）可延长艾滋病患者的生存期并延缓疾病 HIV感染早期患者的病情进展。 虽然 越来越多的HIV-1分离株对 齐多夫定（ZDV）、双脱氧肌苷（ddI）和双脱氧胞苷（ddC）正在被 据报道，病毒耐药的临床意义仍然是 未经证实 尽管如此，很可能出现的病毒池 对逆转录酶抑制剂敏感性降低的人，至少在 部分原因是因为接受这些药物治疗的患者的疾病进展。 因此，在本发明中， 测试药物敏感性可能会越来越重要， 在设计抗逆转录病毒疗法的临床试验和 临床实践 与其他传染病一样， 化疗可以防止耐药性的出现， 毒性 然而，迄今为止报道的体外协同作用研究使用了 组织培养适应的HIV-1菌株可能具有不同的生物学特性， 与临床分离株相比。 作为ACTG病毒学耐药性工作组的参与者，我们建议 开发和测试药物敏感性测试的标准化方案 入组ACTG的患者中的HIV-1低传代临床分离株 ZDV、ddI、ddC和L-697，661等抗逆转录病毒药物的临床试验。 RT 将通过选择性PCR分析耐药菌株的基因 扩增或通过克隆和测序来检测基因型变化 与耐药性有关。 体外选择压力的影响 关于HIV-1感染人群出现高水平耐药性的报告 将研究具有中间药物敏感性或混合基因型的患者。 将在体外测试抗逆转录病毒药物的组合的协同作用 使用对一种或多种病毒敏感性降低的低传代HIV-1分离株 毒品