DLV RESISTANCE MUTATIONS IN HIV REPLICATIONS

HIV 复制中的 DLV 抗性突变

• 批准号: 6170442
• 负责人: Lisa M. Demeter
• 金额: $ 19.13万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-04-01 至 2001-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6170442
• 关键词: RNA directed DNA polymerase; clinical research; delavirdine; drug resistance; gene mutation; genetic polymorphism; human immunodeficiency virus 1; human subject; polymerase chain reaction; reverse transcriptase inhibitors; virus replication

DESCRIPTION (Adapted from the Investigator's Abstract): DLV (Delavirdine) is a highly active, nonnucleoside reverse transcriptase inhibitor(NNRTI) which has been approved for clinical use in HIV infection. In tissue culture experiments, the predominant HIV variant that is selected for encodes a p236L mutation in reverse transcriptase (RT). However, in clinical trials, the P236L mutations is infrequent in clinical isolates, rather Y181C and K103N mutations are more common. This indicates that factors other than those present under tissue culture conditions favor the outgrowth of resistant species. In preliminary studies to explore these factors, the investigators have shown that recombinant virus encoding the P236L mutant has a replication disadvantage, and that recombinant RT with P236L mutant has a replication disadvantage, and that recombinant RT with P236L shows decreased processivity and an increase in pausing. The major goal of this proposal is to further understand the mechanisms for decreased replication fitness of the P236L mutant. The specific aims of the proposal are to: 1) determine the biochemical mechanisms responsible for the defect of the P236L RT, 2) study the replication of kinetics of P236L containing viruses as well as wild-type and other NNRTI mutants, 3) determine the impact of other RT inhibitors on the relative replication fitness of P236L and other mutants, and 4) determine whether there are RT polymorphisms that can compensate for the reduced fitness of P236L.

描述（改编自研究者摘要）：DLV 地拉韦啶是一种高活性的非核苷类逆转录酶 抑制剂（NNRTI）已被批准用于HIV的临床应用 感染 在组织培养实验中，主要的艾滋病毒变体 其被选择用于编码逆转录酶中的p236L突变， （RT）。 然而，在临床试验中，P236L突变并不常见 在临床分离株中，Y181 C和K103 N突变更为常见。 这表明，除了存在于组织下的因素之外， 培养条件有利于抗性物种的生长。 在 为了探索这些因素，研究人员进行了初步研究， 显示编码P236L突变体重组病毒具有复制 具有P236L突变体重组RT具有 复制缺陷，且具有P236L重组RT显示 持续进行能力下降，暂停次数增加。 的主要目标 这一建议是为了进一步了解减少的机制， P236L突变体的复制适应性。 该委员会的具体目标 建议是：1）确定负责的生化机制 P236L RT的缺陷，2）研究复制动力学 含有P236L的病毒以及野生型和其它NNRTI突变体， 3)确定其他RT抑制剂对相对 P236L和其他突变体的复制适应性，以及4）确定是否 RT多态性可以弥补适应性的降低 P236L