Routes of Transmission of HIV in Malawian Mothers

描述(由申请人提供)：这项提案的目的是利用已经从860名艾滋病毒阳性的马拉维孕妇及其后代中收集的样本来研究艾滋病毒母婴传播的生物学机制。我们假设：1)母胎微量输血增加母婴传播的风险，2)母体HIV的多样性是母婴传播的危险因素，3)异源双链跟踪试验可用于区分婴儿肠道外感染HIV和通过粘膜感染的婴儿，以及4)HIV通过细胞相关病毒传播给婴儿。在一项初步研究中，我们测定了脐血中胎盘碱性磷酸酶(PLAP)，这是一种胎盘不通透的高分子量酶，作为母婴微量输血的标志。在对204对母子进行的嵌套病例队列研究中，发现脐带高度升高是分娩期间的危险因素，但不是宫内母婴传播的危险因素。我们的第一个具体目标是通过a)从全队列中测量脐带血清中的PLAP，以及b)开发和使用第二种基于遗传多态的母亲胎儿微量输血方法来扩展这些观察。在第二个目标中，我们将使用异源双链跟踪分析记录母亲和婴儿的病毒多样性，并评估母亲多样性和母婴传播之间的相关性；此外，我们将使用婴儿艾滋病毒种群多样性数据，以及特定目标1的数据，以确定婴儿感染是由于粘膜接触还是通过母亲对胎儿循环的污染直接接种造成的。在第三个目标中，我们将比较母体、脐带和新生儿血浆和细胞相关病毒的特征，以确定这两个部分对传播的相对重要性。因此，该项目的结果将建议一个与艾滋病毒垂直传播相关的媒介、途径和母体因素的综合模型。

DESCRIPTION (provided by applicant): The aim of this proposal is to study the biological mechanism of mother-to-child transmission (MTCT) of HIV using samples already collected from a well-characterized cohort of 860 HIV(+) pregnant Malawian women and their offspring. We hypothesize that: 1) the risk of MTCT is increased as a result of increased maternal-fetal microtransfusion, 2) maternal HIV diversity is a risk factor for MTCT, 3) heteroduplex tracking assays can be used to distinguish infants infected with HIV parenterally versus infants infected through mucosal membranes and 4) HIV is transmitted to infants through cell-associated virus. In a preliminary study, we measured placental alkaline phosphatase (PLAP), a placenta-impermeable high-molecular weight enzyme, in umbilical serum as a marker for maternal-fetal microtransfusion. In a nested case-cohort study of 204 mother-child pairs, elevated umbilical PLAP was found to be is a risk factor for intrapartum, but not intrauterine MTCT. Our first specific aim is to extend these observations by a) measuring PLAP in the umbilical cord sera from the full cohort, and b) developing and using a second method for maternal fetal microtransfusion based on genetic polymorphisms. In the second aim we will document maternal and infant viral diversity using heteroduplex tracking assays and assess the correlation between maternal diversity and MTCT; furthermore, we will use the infant HIV population diversity data, along with the data from Specific Aim 1, to determine if infant infections are a result of a mucosal exposure or direct inoculation via maternal contamination of fetal circulation. In the third Aim we will compare the profiles of maternal, umbilical and neonatal plasma^ and cell-associated virus to determine the relative importance of the two compartments to transmission. Thus, the results of this project will suggest a comprehensive model of the vector, the route, and the maternal factors associated with HIV vertical transmission.