Reservoirs of drug-resistant HIV-1

描述(申请人提供)：用高效抗逆转录病毒疗法(HAART)治疗HIV-1感染可以显著改善免疫功能和一般健康。然而，由于耐药病毒，相当大比例的HIV-1感染者没有从HAART中完全受益。一旦被选中，耐药病毒被认为会持续存在，即使在无法检测到的情况下也是如此，而且由于许多可用药物之间的交叉耐药，它往往会限制后续HAART的疗效。我们对耐药病毒库的建立和持久性的了解尚不完整，然而，正是这些库是我们需要了解和克服的，才能成功治疗大部分艾滋病毒-1感染者。单剂量奈韦拉平已被许多项目采用，以减少艾滋病毒-1母婴传播(MTCT)，因为其疗效(50%)以非常低的成本。单剂量奈韦拉平在暴露的妇女和婴儿中选择耐药突变。即使这些突变体在通过共识测序进行评估时“褪色”，最近的泰国研究表明，它们可能会以一种时间依赖的方式损害后续基于NVP的HAART(NVP-HAART)的疗效(Jourdain，第11 CROI，2004；LB41)。我们和其他人的数据表明，大多数长寿的病毒库是在初次感染期间建立的。我们假设，在抗逆转录病毒药物的选择压力下，耐药突变株成为长寿病毒库的一部分，与病毒复制的数量和持续时间相称。当药物压力是短期的，例如单剂量奈韦拉平，我们假设所选择的突变体主要驻留在短期的淋巴细胞中，并最小限度地干扰长期的病毒库。随着短命细胞的衰变，我们假设，它们最终会维持在临床上微不足道的水平。为了验证这些假设，我们建议：目的1：在莫桑比克婴儿中前瞻性地确定单剂NVP相对于婴儿感染HIV-1的时间(即急性感染后或感染期间的NVP)是否会影响所选择的NVP耐药突变的数量和持续时间。目的2：泰语学习。分析(与泰国合作者一起回顾)产后10天、6周、12周或HAART开始时PBMC中耐NVP的HIV-1 DNA水平是否预示着随后的病毒学失败。莫桑比克研究报告1.)前瞻性地量化单剂量服用NVP预防婴儿的莫桑比克产后妇女PBMC中耐NVP的HIV-1 DNA的选择和衰退。2.)在一项对莫桑比克妇女的探索性研究中，确定NVP-HAART期间血浆和PBMC中NVP突变的重新点燃或“病毒学衰竭”是否与以下因素有关：单剂NVP注射和启动NVP-HAART之间的时间间隔，或启动HAART时PBMC中NVP突变的水平。建议的研究应能深入了解与单剂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制定补充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.