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

描述（由申请人提供）：母乳喂养可占儿科艾滋病毒感染的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，人们买不起配方奶粉，而且由于肠胃炎和营养不良等传染病，配方奶粉的发病率和死亡率很高。因此，目前的世卫组织指南建议来自最不发达地区的感染艾滋病毒的母亲母乳喂养婴儿。多项观察性前瞻性研究表明，与混合喂养（MF）的婴儿相比，纯母乳喂养（EBF）可将母婴传播（MTCT）的风险降低2至10倍。在发达国家和发展中国家，EBF甚至降低了未接触艾滋病毒的婴儿的发病率。在发达国家和发展中国家，EBF甚至降低了未接触艾滋病毒的婴儿的发病率。然而，母亲很难维持EBF，婴儿在4至6个月大后才给予辅食。此外，一项4个月时快速断奶的EBF研究显示，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，可以采取干预措施，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，非母乳液体和固体的添加改变了婴儿的粘膜或上消化道的免疫屏障。这可能导致免疫细胞激活，粘膜HIV靶细胞增加，或肠道微生物易位增加，可能是由于粘膜完整性受损或胃肠道和/或全身感染增加。该项目通过测量不同喂养方式婴儿血液和唾液中的免疫激活，验证了混合喂养婴儿与EBF婴儿相比在粘膜和全身隔室中显示免疫激活证据的假设（目的1）。免疫激活的增加可能是由于生命早期肠道共生生物的变化（目的2）。因此，这些实验将分析这些婴儿粪便中的微生物。这种激活可能源于混合饲养引起的粘膜损伤或感染，以及由此引起的细菌产物在肠道粘膜上的易位进入体循环（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周龄和14周龄）对这些婴儿进行评估，本研究计划评估EBF婴儿降低艾滋病毒感染风险的机制，并发现混合喂养期间预防MTCT的目标，并潜在地使全球所有无法EBF的婴儿受益。

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.