HIV-1 Evolution and Functional Correlates of MTCT

描述（由申请人提供）：HIV 的粘膜传播涉及强烈的瓶颈效应，并且最常见的是传播单一创始人病毒。相对贡献 随机（随机）选择与特定病毒和宿主特征主动选择的比较 这个瓶颈还不清楚。通过母乳喂养进行的 HIV-1 母婴传播 (MTCT) 很容易确定传播对和婴儿感染的时间，为解决这些重要且尚未解决的问题提供了一个指导性模型。我们将使用来自大量、特征明确的 HIV-1 感染津巴布韦妇女的系列样本，这些妇女通过母乳传播 HIV-1。该队列包括慢性 HIV-1 感染女性（CI；N=35）和产后原发性 HIV-1 感染女性（急性感染，AI；N=13）。我们将系统发育学（基于深度测序数据的频率分析）与功能分析（CD4和辅助受体的使用、进入动力学、中和敏感性）相结合，定量和全面地分析创始病毒与母血或母乳变异的关系，量化随机选择与主动选择的相对贡献，识别包膜（env）上的选择压力，区分选择压力在传播瓶颈期间何时起作用，并确定创始病毒变体是否比其他非传播变体更适应病毒传播。产后母婴传播。描述传播变异的生物学特性以及绘制这些生物学特性的遗传基础图谱，应该可以增进对 HIV-1 进入和 HIV-1 进入抑制剂作用机制的理解。这些研究还将提高我们对自体中和抗体和先天因素在两个不同且相关的解剖区室（血液中抗体水平高，母乳中抗体水平低得多）中施加的体内选择压力以及中和敏感性或逃逸在传播中的潜在作用的理解。最后，这些研究将具体揭示增加血液或母乳的中和活性（例如，通过被动或主动免疫）或针对其他环境功能特性（向性、传染性）是否有望阻止妇女和儿童的原发感染。

DESCRIPTION (provided by applicant): Mucosal transmission of HIV involves a strong bottleneck effect and most often, a single founder virus is transmitted. The relative contributions of stochastic (random) selection vs. active selection by specific viral and host characteristics to this bottleneck are unclear. Mother-to-child HIV-1 transmission (MTCT) through breastfeeding, in which transmission pairs and timing of infant infection are readily identified, provides an instructive model to address these important and unresolved questions. We will use serial samples from a large, well characterized cohort of HIV-1 infected Zimbabwean women who transmitted HIV-1 through breastmilk. This cohort includes women with chronic HIV-1 infection (CI; N=35), and women who acquired primary HIV-1 infection post-partum (acute infection, AI; N=13). We combine phylogenetics (with frequency analyses based on deep sequencing data) with functional assays (CD4 and co-receptor use, entry kinetics, neutralization sensitivity), to quantitatively and comprehensively analyze the relationship of founder viruses to maternal blood or breastmilk variants, quantify the relative contributions of stochastic vs. active selectio, identify selection pressures on envelope (env), differentiate when selection pressures may operate during the transmission bottleneck, and determine whether founder env variants are better adapted than other non- transmitted variants for postnatal MTCT. Delineation of the biologic properties of transmitted variants along with mapping the genetic bases of these biologic properties, should improve understanding of HIV-1 entry and the mechanisms of action of HIV-1 entry inhibitors. These studies will also improve our understanding of the in vivo selective pressures exerted by autologous neutralizing antibodies and innate factors in two distinct and relevant anatomic compartments (blood, where levels of antibodies are high, and breastmilk, where they are much lower) and the potential role of neutralization sensitivity or escape in transmission. Finally, these studies will specifically reveal whether increasing the neutralizing activity of blood or breastmilk (e.g., through passive or active immunization) or targeting other Env functional properties (tropism, infectivity) hold promise to block primary infection of women and children.