DEVELOPMENTAL VIROLOGY

HIV-1必需酶逆转的核苷类抑制剂 转录酶(RT)延长艾滋病患者的生存时间并延缓疾病 艾滋病毒感染早期患者的进展情况。尽管有一个 对艾滋病易感性降低的艾滋病毒-1分离株数量增加 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存在 未经证实。然而，很可能出现了一个病毒池 对RT抑制剂敏感性降低是原因之一，至少在 部分，对于使用这些药物治疗的患者的疾病进展。因此， 药物敏感性测试可能会承担越来越重要的任务 在抗逆转录病毒治疗的临床试验设计中的地位 临床实践。就像在其他传染病中一样，使用联合 化疗可能会预防耐药性的出现并将其降至最低 毒性。然而，迄今为止报道的体外协同作用研究使用了 可能具有不同生物学特性的组织培养适应株HIV-1 与临床分离株的特性进行比较。 作为ACTG病毒学耐药性工作组的成员，我们建议 制定和测试药物敏感性测试的标准化方案 来自ACTG患者的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试验。RT 来自耐药菌株的基因将通过选择性聚合酶链式反应进行分析 或通过克隆和测序来检测基因类型的变化 与抗药性有关。体外选择压力的影响 HIV-1人群中出现高水平耐药性的研究 对药物敏感性中等或混合基因型的患者将进行研究。 抗逆转录病毒药物的组合将在体外进行协同作用测试 使用对一种或多种敏感性降低的低传代HIV-1分离株 毒品。

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.