Assessing feeding practices, immune activation, and HIV risk in African infants

描述（由申请人提供）：母乳喂养可占儿童艾滋病毒感染的39%。在发达国家，感染艾滋病毒的母亲给婴儿喂配方奶粉，以防止产后艾滋病毒传播。然而，在发展中世界的许多地方，配方奶是负担不起的，并且与肠胃炎和营养不良等传染病造成的高发病率和死亡率有关。因此，世卫组织目前的指导方针建议来自最不发达环境的艾滋病毒感染母亲母乳喂养婴儿。多项观察性、前瞻性研究表明，纯母乳喂养（EBF）与除母乳外还混合喂养（MF）其他牛奶、液体或固体的婴儿相比，可将母婴传播（MTCT）的风险降低2至10倍。EBF降低发病率，即使在非艾滋病毒暴露的婴儿在发达国家和发展中国家的环境。EBF降低发病率，即使在非艾滋病毒暴露的婴儿在发达国家和发展中国家的环境。然而，EBF对母亲来说很难维持，婴儿在四到六个月大后才给予补充食物。此外，一项关于四个月快速断奶的EBF研究表明，未感染婴儿的发病率很高。了解与这种风险增加相关的机制可能会导致干预措施，使混合喂养和补充喂养对婴儿更安全。EBF的保护作用的一个可能的解释是，添加非母乳液体和固体改变了婴儿上胃肠道的粘膜或免疫屏障。这可能导致免疫细胞活化，粘膜上的HIV靶细胞增加，或肠道微生物移位增加，可能是由于粘膜完整性受损或胃肠道和/或全身感染增加。本项目通过测量不同喂养方式的婴儿血液和唾液中的免疫激活，检验混合喂养婴儿与EBF婴儿（目标1）相比时在粘膜和全身隔室中显示免疫激活证据的假设。这种免疫激活的增加可能是由于生命早期肠道微生物的变化（目的2）。因此，这些实验将分析这些婴儿粪便中的微生物。这种激活可能来源于混合喂养诱导的粘膜损伤或感染以及随后细菌产物穿过肠粘膜进入体循环的易位（目的3），因此我们的实验将测量血液中的微生物产物。通过在多个时间点（6和14周龄）对这些婴儿进行评估，本研究计划评估EBF婴儿降低HIV感染风险的机制，并揭示混合喂养期间预防MTCT的目标，并可能使全球所有无法EBF的婴儿受益。 公共卫生相关性：这些研究旨在从机制上辨别为什么混合喂养的婴儿中HIV传播增加。这些数据有可能导致未来的干预研究，以预防产后母婴传播，如特异性免疫干预，以下调靶细胞的数量，或通过有针对性的肠道微生物疗法，通过使用益生菌补充混合喂养的婴儿。

DESCRIPTION (provided by applicant): Breastfeeding can account for up to 39% of pediatric HIV infections. In developed countries, HIV-infected mothers feed formula to their infants to prevent postpartum HIV transmission. However, in many parts of the developing world, formula is unaffordable and is associated with high morbidity and mortality due to infectious diseases such as gastroenteritis and malnourishment. Therefore, the current WHO guidelines recommend that HIV-infected mothers from most underdeveloped settings breastfeed their infants. Multiple observational, prospective studies have shown that exclusive breastfeeding (EBF) reduces the risk of mother-to-child- transmission (MTCT) two to tenfold compared to infants that are mixed-fed (MF) with other milks, liquids, or solids in addition to breast. EBF decreases morbidity even in non-HIV-exposed infants in both developed and developing settings. EBF decreases morbidity even in non-HIV-exposed infants in both developed and developing settings. However, EBF is difficult for mothers to maintain, and infants are given complementary foods after four to six months of age. In addition, a study of EBF with rapid weaning at four months showed high morbidity in the uninfected infants. Understanding the mechanisms associated with this increased risk could lead to interventions to make mixed feeding and complementary feeding safer for infants. One potential explanation for the protective effect of EBF is that the addition of non-breast milk liquids and solids alters the infant's mucosal or immunologic barriers of the upper gastrointestinal tract. This could lead to immune cell activation with an increase HIV target cells at the mucosa, or increased microbial translocation across the gut, possibly due to compromised mucosal integrity or increased gastrointestinal and/or systemic infections. This project tests the hypothesis that mixed fed infants will display evidence for immune activation within both mucosal and systemic compartments when compared to EBF infants (Aim 1), by measuring immune activation in the blood and in saliva of infants with different feeding practices. This increase in immune activation could be due to changes in the gut commensal organisms in early life (Aim 2). Therefore, these experiments will analyze the microbes in stool of these babies. This activation is possibly derived from mixed feeding- induced mucosal impairment or infections and the consequent translocation of bacterial products across the gut mucosa into the systemic circulation (Aim 3), therefore our experiments will measure microbial products in blood. Through assessment of these infants at multiple time points (6 and 14 weeks of age), this study plans to evaluate the mechanisms conferring EBF infants a reduced risk of HIV infection, and to uncover targets for MTCT prevention during mixed feeding, and to potentially benefit all infants globally who cannot EBF. PUBLIC HEALTH RELEVANCE: These studies are designed to mechanistically discern why HIV transmission is increased in mixed fed infants. These data have the potential to lead to future studies of interventions to prevent postpartum MTCT, such as specific immune interventions to down-modulate the numbers of target cells or through targeted gut microbial therapies through the use of probiotic supplementation for mixed fed infants.