Vitamins, Breast Milk HIV Shedding and Child Health

描述（由申请人提供）：我们已经证明，在感染艾滋病毒的妇女怀孕和哺乳期间补充维生素B、C和E与疾病晚期妇女母乳喂养传播率较低有关，而补充维生素A与总体风险增加有关。鉴于在许多发展中国家，向感染艾滋病毒状况不明的哺乳期妇女补充维生素A正成为一种普遍的公共卫生做法，因此迫切需要确定维生素A对艾滋病毒传播产生不利影响的生物学机制。一种可能的解释机制是，维生素补充剂可能会影响母乳中无细胞和/或细胞相关艾滋病毒的脱落。初步分析支持这一观点。我们建议在坦桑尼亚参加一项随机临床试验的771名妇女的子样本中，研究在怀孕和哺乳期间给HIV-1感染妇女补充维生素（A vs.不补充A和多种维生素（B、C和E） vs.不补充多种维生素）对母乳中HIV-1病毒和原病毒载量的影响。这种影响将在三个时间点确定：分娩（n=592）、分娩后3个月（n=570）和分娩后6个月（n=516）。我们还将研究其他机制来解释维生素补充剂对母乳喂养传播的影响；这些研究包括：1)补充剂对亚临床乳腺炎风险的影响（通过Na/K比值测量）；2)维甲酸和/或β -胡萝卜素对体外CCR5表达和病毒复制的影响。接下来，我们打算研究维生素补充剂对分娩时、分娩后3个月和6个月母乳中维生素A、B12和E浓度的影响，以及母乳中这些维生素浓度与婴儿头两年发病率和死亡率之间的关系。最后，我们建议研究母乳中HIV病毒和原病毒载量与产后HIV传播风险之间的关系。该提案的一个显著优势是，它将允许我们使用已经收集并适当存储在大型正在进行的试验背景下的数据和生物样本来检查各种相关的研究问题，并且具有高随访率和依从性。

DESCRIPTION (provided by applicant): We have shown that supplementation with vitamins B, C, and E during pregnancy and lactation to HIV-infected women is related to lower rates of breastfeeding transmission among women in advanced stage of disease, whereas vitamin A supplementation is associated with an overall increased risk. Given that vitamin A supplementation to lactating women of unknown HIV status is becoming a widespread public health practice in many developing countries, it is urgent to identify the biological mechanisms that underlie the adverse effect of vitamin A on HIV transmission. One potential explanatory mechanism is that vitamin supplements might affect the shedding of cell-free and/or cell-associated HIV in breast milk. Preliminary analyses support this notion. We propose to examine the effect of vitamin supplements (A vs. no A and multivitamins (B, C, and E) vs. no multivitamins) administered during pregnancy and lactation to HIV-1 infected women on HIV-1 viral and proviral load in breast milk, in a sub-sample of 771 women who participated in a randomized clinical trial in Tanzania. This effect will be ascertained at three time points: delivery (n=592), 3 months after delivery (n=570), and 6 months after delivery (n=516). We will also study other mechanisms to explain the effect of vitamin supplements on breastfeeding transmission; these include 1) the effect of supplements on the risk of sub-clinical mastitis as measured by the Na/K ratio, and 2) the effect of retinoic acid and/or beta-carotene on expression of CCR5 and viral replication in vitro. Next, we propose to examine the effect of vitamin supplements on the concentration of vitamins A, B12, and E in breast milk at delivery, 3, and 6 moths thereafter, and the associations between the concentration of these vitamins in breast milk and child morbidity and mortality during the first two years. Finally, we propose to examine the associations between HIV viral and proviral load in breast milk and the risk of post-natal transmission of HIV. A significant advantage of this proposal is that it would allow us to examine various relevant research questions using data and biological samples that have been already collected and appropriately stored in the context of a large ongoing trial with high rates of follow-up and compliance.