DLV RESISTANCE MUTATIONS IN HIV REPLICATIONS

描述(改编自《调查员摘要》)：DLV (地拉韦定)是一种高活性的非核苷逆转录酶 已获准临床使用的HIV抑制剂(NNRTI) 感染。在组织培养实验中，占主导地位的艾滋病毒变异株 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，Y181C和K103N突变更为常见。 这表明，组织下存在的因素以外的因素 培养条件有利于抗性物种的生长。在……里面 为了探索这些因素的初步研究，调查人员 表明编码P236L突变体的重组病毒具有复制能力 缺点是，与P236L突变体重组RT具有 复制劣势，与P236L重组RT显示 过程性降低，停顿增加。的主要目标是 这一建议是为了进一步了解减少的机制 P236L突变体的复制适合性。《公约》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P236L RT的复制动力学 P236L含有病毒以及野生型和其他NNRTI突变体， 3)确定其他RT抑制剂对相对分子质量的影响 P236L和其他突变体的复制适合性，以及4)决定 有一些RT多态可以补偿降低的适应性 P236L。

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.