Oral Transmission of HIV through Breastfeeding

描述(申请人提供)：由感染艾滋病毒的母亲哺乳的婴儿有通过母乳喂养感染艾滋病毒的风险。在没有干预措施的情况下，大约14%的母乳喂养婴儿将通过这一途径感染。这种相对较低的传播率令人惊讶，因为婴儿在18个月或更长的时间里每天多次摄入含有病毒的母乳。婴儿经口传播的低效耐人寻味。我们假设，人类母乳中的免疫调节成分有助于解释这种低传播率。影响上皮完整性的先天免疫因素可能通过调节母乳中病毒的数量和传染性和/或通过婴儿肠道中的被动免疫过程来影响传播，以防止感染的建立。这些因素也可能减少激活，导致感染艾滋病毒的母乳喂养婴儿的疾病进展缓慢。我们推测，人乳低聚糖(HMO)、可溶性Toll样受体(STLR)和其他先天免疫因子可能在防止艾滋病毒通过母乳喂养传播和调节疾病进展方面发挥作用。母乳喂养的婴儿为研究这些新因素提供了一个独特的人类挑战模型。利用赞比亚感染艾滋病毒的母亲所生的900多名母乳喂养婴儿的现有临床样本，我们将确定母乳中HMO、sTLR和其他粘膜免疫成分的特征，并调查它们在婴儿经口传播艾滋病毒中的作用。除了已经收集的临床数据外，我们还将纳入对母乳中艾滋病毒RNA和DNA脱落的详细病毒学研究。我们已经组建了一个在粘膜液中具有特定天然免疫专业知识的多学科科学团队，他们结合大型临床数据库和病毒学研究，将允许进行严格和强大的流行病学分析，以调查：(1)母乳中天然免疫因子浓度较高是否与较低的母乳喂养相关艾滋病毒传播率有关，与母乳中HIV-1 RNA和DNA浓度无关，特别是在因牙齿发育和/或口腔鹅口疮而导致口腔粘膜受损的婴儿中；(2)基于外周血中的HIV RNA和其他母体疾病严重程度的标志，母乳中的天然免疫因素是否相对于预期的脱落减少了母乳中的粘膜病毒脱落；以及(3)在感染艾滋病毒的儿童中，母乳中天然免疫因素浓度较高是否与他们在母乳喂养但不是在他们断奶后的疾病进展缓慢有关。这些研究将允许在体内评估抗HIV天然黏膜免疫的潜在作用，这将为利用粘膜天然免疫的潜在HIV疫苗提供信息。 与公共卫生相关：我们建议表征先天免疫的新成分，包括人类乳寡糖、可溶性Toll样受体和来自艾滋病毒感染母亲的母乳喂养婴儿队列的其他成分。我们将评估这些因素在减少通过母乳喂养的口腔传播、防止受感染的母乳喂养婴儿的粘膜病毒脱落和延缓疾病进展方面的作用。

DESCRIPTION (provided by applicant): Infants who are breastfed by their HIV-infected mothers are at risk of acquiring HIV infection through breastfeeding. In the absence of interventions, about 14% of breastfed infants will acquire infection via this route. This relatively low transmission rate is surprising since infants ingest virus-containing breast milk many times a day over 18 or more months. The inefficiency of oral transmission in infants is intriguing. We hypothesize that immunomodulatory components of human breast milk help explain this low rate of transmission. Innate immune factors that influence epithelial integrity may affect transmission by regulating the amount and infectivity of virus in breast milk and/or through passive immune processes in the infant gut preventing the establishment of infection. These factors may also reduce activation leading to slower disease progression in HIV-infected breast-fed infants. We hypothesize that human milk oligosaccharides (HMO), soluble toll-like receptors (sTLR) and other innate immune factors may play a role in preventing oral transmission of HIV via breastfeeding and modulate disease progression. The breastfed infant provides a unique human challenge model to investigate these novel factors. Using existing clinical samples from a cohort of over 900 breastfed infants born to HIV-infected mothers in Zambia, we will characterize HMO, sTLR and other components of mucosal immunity in breast milk and investigate their role in oral HIV transmission in infants. In addition to the already collected clinical data, we will incorporate detailed virologic studies of HIV RNA and DNA shedding in breast milk. We have put together a multi-disciplinary scientific team with specific expertise in innate immunity in mucosal fluids who, combined with the large clinical database and virologic studies, will allow rigorous and powerful epidemiologic analyses to investigate: (1) whether higher concentrations of innate immune factors in breast milk are associated with lower rates of breast feeding- associated HIV transmission, independent of HIV-1 RNA and DNA concentrations in breast milk and especially among infants who have disruptions in the oral mucosa due to teeth development and/or oral thrush; (2) whether innate immune factors in breast milk reduce mucosal viral shedding in breast milk relative to expected shedding based on HIV RNA in peripheral blood and other markers of the severity of maternal disease including CD4 counts; and (3) whether higher concentrations of innate immune factors in breast milk are associated with slower disease progression in HIV-infected children while they are being breastfed but not after they are weaned. These studies will allow an in vivo evaluation of the potential role of anti-HIV innate mucosal immunity that will be informative for potential HIV vaccines that harness mucosal innate immunity. PUBLIC HEALTH RELEVANCE: We propose to characterize novel components of innate immunity, including human milk oligosaccharides, soluble toll-like receptors, and others from a cohort of breast-fed infants of HIV-infected mothers. We will evaluate the role of these factors in reducing oral transmission via breastfeeding, preventing mucosal viral shedding and delaying disease progression in infected breast-fed infants.