Fitness of Enfuvirtide-(T-20)-Resistant HIV-1

恩夫韦肽 (T-20) 抗性 HIV-1 的适用性

• 批准号: 6696373
• 负责人: Daniel R. Kuritzkes
• 金额: $ 17.3万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-07-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6696373
• 关键词: CD4 molecule; HIV envelope protein gp41; SDS polyacrylamide gel electrophoresis; antiAIDS agent; antiviral agents; clinical research; drug resistance; gene mutation; human immunodeficiency virus 1; human tissue; nucleoside inhibitor; polymerase chain reaction; protease inhibitor; site directed mutagenesis; tissue /cell culture; virulence

DESCRIPTION (provided by applicant): Mutations in human immunodeficiency virus type 1 (HIV-1) that confer drug resistance may also impair replication capacity of the virus. Reduced replication capacity of multi-drug resistant viruses may explain, in part, the persistent immunologic benefits of protease inhibitor-containing regimens in the setting of virologic failure. Plasma virus titers remain significantly below the viral set point due to the combined effects of the residual activity of the failing regimen and the reduced replication capacity compared to wild-type. Removal of selective pressure by treatment interruption leads to re-emergence of the fitter wild-type virus that is associated with a rise in virus load and fall in CD4 cell count. Enfuvirtide (T-20) is a novel HIV- 1 entry inhibitor with potent activity in vitro and in vivo. This 36-amino acid peptide blocks HIV-1 entry by binding to the first heptad repeat (HR-1) of the gp41 ectodomain, thereby preventing formation of a hairpin loop that is essential for virus-cell fusion. Mutations at several positions in HR-1 confer resistance to T-20. Although resistance to T-20 can develop quickly, data from clinical studies suggest that T-20 remains at least partially active despite emergence of T-20-resistant virus. Preliminary data show that these viruses are less fit than wild-type in growth competition assays in the absence of drug using a novel recombinant marker virus assay developed in our laboratory. We therefore propose a series of experiments to characterize further the effects of T-20 resistance mutations on HIV-1 fitness, kinetics of HIV-1 entry, and virulence. Specific aims of these experiments are: 1) To compare fitness of T-20 -resistant viruses in presence and absence of drug; 2) To test the hypothesis that fitness loss associated with T-20 resistance is significantly correlated with persistent antiviral activity of T-20; and 3) To test the hypothesis that fitness differences associated with T-20 resistance mutations are due to differences in the rate of virus-cell fusion. Results of these studies will provide a deeper understanding of the molecular, virologic, and clinical consequences ofT-20 resistance, and may help guide the use of T-20 in salvage therapy.

描述（由申请方提供）：人类免疫缺陷病毒1型（HIV-1）中产生耐药性的突变也可能损害病毒的复制能力。多药耐药病毒复制能力的降低可能部分解释了在病毒学失败的情况下，含蛋白酶底物方案的持续免疫学益处。血浆病毒滴度保持显著低于病毒设定点，这是由于失败方案的残余活性和与野生型相比降低的复制能力的组合效应。通过治疗中断消除选择性压力导致更适合的野生型病毒重新出现，这与病毒载量增加和CD 4细胞计数下降有关。恩夫韦肽（Enfuvirtide，T-20）是一种新型的HIV- 1进入抑制剂，具有较强的体内外活性。这种由36个氨基酸组成的肽通过与gp 41胞外域的第一个七肽重复序列（HR-1）结合来阻止HIV-1进入，从而阻止病毒-细胞融合所必需的发夹环的形成。HR-1中几个位置的突变赋予对T-20的抗性。虽然对T-20的耐药性可以迅速发展，但临床研究的数据表明，尽管出现了T-20耐药病毒，但T-20仍然至少部分具有活性。初步数据表明，这些病毒是不适合比野生型在生长竞争试验中使用一种新的重组标记病毒检测在我们的实验室开发的药物的情况下。因此，我们提出了一系列的实验，以进一步表征T-20耐药突变对HIV-1适应性，HIV-1进入动力学和毒力的影响。这些实验的具体目的是：1）比较存在和不存在药物的情况下T-20抗性病毒的适合度; 2）检验与T-20抗性相关的适合度损失与T-20的持续抗病毒活性显著相关的假设;和3）检验与T-20抗性突变相关的适应性差异是由于病毒-细胞融合速率的差异的假设。这些研究的结果将为T-20耐药的分子、病毒学和临床后果提供更深入的了解，并可能有助于指导T-20在挽救治疗中的使用。