HIV-1 Evolution and Functional Correlates of MTCT

描述（由申请人提供）：HIV的粘液传播涉及强烈的瓶颈效应，最常见的是传播单一的创始病毒。的相对贡献 随机（随机）选择与通过特定病毒和宿主特征进行的主动选择， 这个瓶颈还不清楚。通过母乳喂养进行的艾滋病毒1型母婴传播很容易确定传播对和婴儿感染的时间，为解决这些重要和尚未解决的问题提供了一个有指导意义的模式。我们将使用来自一个大的，充分表征的HIV-1感染的津巴布韦妇女谁通过母乳传播HIV-1队列的系列样本。该队列包括患有慢性HIV-1感染的妇女（CI; N=35）和产后获得原发性HIV-1感染的妇女（急性感染，AI; N=13）。我们将联合收割机（基于深度测序数据的频率分析）（CD 4和共受体使用、进入动力学、中和敏感性），以定量和全面地分析创始病毒与母体血液或母乳变体的关系，量化随机选择与主动选择的相对贡献，鉴定对包膜（env）的选择压力，区分选择压力在传播瓶颈期间何时起作用，并确定创始者env变体是否比其他非传播变体更适合于出生后MTCT。描述传播变异体的生物学特性沿着绘制这些生物学特性的遗传基础，将提高对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子在两个不同且相关的解剖隔室（血液，抗体水平高，母乳，抗体水平低得多）中施加的体内选择性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接种）或靶向其他Env功能特性（嗜性、传染性）有望阻断妇女和儿童的原发性感染。

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.