Reservoirs of drug-resistant HIV-1

描述（由申请人提供）：使用高效抗逆转录病毒疗法（HAART）治疗HIV-1感染可显著改善免疫功能和整体健康。然而，很大一部分HIV-1感染者由于耐药病毒而不能从HAART疗法中充分受益。一旦被选中，耐药病毒被认为会持续存在，即使无法检测到，而且由于许多现有药物之间的交叉耐药性，它往往限制了随后的HAART治疗的效果。我们对耐药病毒储存库的建立和持续存在的了解是不完整的，然而，我们需要了解和克服这些储存库，以成功治疗大部分HIV-1感染人群。单剂量奈韦拉平已被许多项目采用，以减少HIV-1母婴传播（MTCT），因为它的效率（50%）在非常低的成本。单剂量奈韦拉平选择在暴露的妇女和婴儿耐药突变体。尽管这些突变体在一致测序评估时“消退”，但泰国最近的研究表明，它们可能会以一种时间依赖的方式损害随后基于nvp的HAART （NVP-HAART）的疗效{Jourdain， 11 CROI, 2004；磅41)。我们和其他人的数据表明，大多数长寿命的病毒库是在初次感染期间建立的。我们假设耐药突变体在抗逆转录病毒的选择性压力下成为与病毒复制的数量和持续时间相称的长寿命储存库的一部分。当药物压力是短期的，如单剂量奈韦拉平，我们假设选择的突变体主要存在于寿命较短的淋巴细胞中，对寿命较长的病毒库的干扰最小。随着短寿命细胞的衰变，我们假设，它们最终会维持在临床无关紧要的水平。为了验证这些假设，我们提出：目的1：在莫桑比克婴儿中前瞻性地确定单剂量NVP的时间相对于婴儿感染HIV-1的时间（即急性感染后或期间的NVP）是否会影响NVP抗性突变体的选择数量及其持续时间。目标2：泰国研究。分析（与泰国合作者）产后10天、6周和12周或开始HAART治疗时PBMC中抗nvp的HIV-1 DNA水平是否预示着随后的“病毒学失败”。莫桑比克研究1)定量预测服用单剂量NVP预防其婴儿的莫桑比克产后妇女PBMC中NVP耐药HIV-1 DNA的选择和衰减。2)。在一项针对莫桑比克妇女的探索性研究中，确定在NVP-HAART期间血浆和PBMC中NVP突变体的重新点燃或“病毒学失败”是否与：单剂量NVP给药和开始NVP-HAART之间的时间间隔，或HAART开始时PBMC中NVP突变体的水平有关。拟议的研究应该能够深入了解与单剂量NVP相关的NVP耐药病毒库的选择和持久性，以及这些突变体的临床效果。这些数据有助于为妇女和儿童建立补充性的母婴传播预防方案和HAART。

DESCRIPTION (provided by applicant): Treatment of HIV-1 infection with highly active antiretroviral therapy (HAART) can markedly improve immune function and general health. However, a significant proportion of HIV-1 infected individuals do not fully benefit from HAART due to drug-resistant virus. Once selected, drug-resistant virus is thought to persists, even when undetectable, and often it limits the efficacy of subsequent HAART due to cross-resistance between many available drugs. Our knowledge regarding the establishment and persistence of reservoirs of drug-resistant virus is incomplete, yet, it is these reservoirs that we need to understand and overcome for successful treatment of a large segment of the HIV-1 - infected population. Single-dose nevirapine has been adopted by many programs to reduce mother-to-child transmission of HIV-1 (MTCT) due to its efficacy (50%) at a very low cost. Single-dose nevirapine selects for drug resistant mutants in exposed women and infants. Even though these mutants "fade" when assessed by consensus sequencing, recent Thai studies suggest that they may compromise the efficacy of subsequent NVP-based HAART (NVP-HAART), perhaps in a time-dependent fashion {Jourdain, 11th CROI, 2004; LB 41). We and others have data suggesting that most of the long-lived viral reservoirs are established during primary infection. We hypothesize that drug-resistant mutants become part of the long-lived reservoirs commensurate with the amount and duration of viral replication during selective pressure by antiretrovirals. When drug pressure is short-term, such as with single-dose nevirapine, we hypothesize that the selected mutants primarily reside in short-lived lymphocytes, and minimally perturb the long-lived viral reservoirs. As the short-lived cells decay, we hypothesize, that they eventually persist at clinically insignificant levels. To test these hypotheses, we propose to: Aim 1: Determine prospectively in Mozambican infants if the timing of single-dose NVP relative to the time of HIV-1 infection in infants (i.e. NVP after or during acute infection) affects the quantity of NVP-resistant mutants selected and the duration of their persistence. Aim 2: Thai study. Analyze (retrospectively, with Thai collaborators) if the level of NVP-resistant HIV-1 DNA in PBMC, at 10 d, 6 and 12 wk postpartum or at the time HAART is initiated, is predictive of subsequent "virologic failure". Mozambican studies 1.) Quantify prospectively the selection and decay of NVP-resistant HIV-1 DNA in PBMC of Mozambican postpartum women taking single-dose NVP for prophylaxis of their infants. 2.) Determine in an exploratory study of Mozambican women if the rekindling of NVP-mutants in plasma and PBMC or "virologic failure" during NVP-HAART is related to: the time interval between the administration of single-dose NVP and initiation of NVP-HAART, or the level of NVP-mutants in PBMC when HAART is initiated. The proposed studies should provide insight into the selection and persistence of NVP-resistant viral reservoirs associated with single-dose NVP, and the clinical effects of these mutants. These data assist in establishing complementary MTCT prophylaxis regimens and HAART for women and children.