Oral Transmission of HIV through Breastfeeding

说明（由申请人提供）：由感染艾滋病毒的母亲母乳喂养的婴儿有通过母乳喂养感染艾滋病毒的风险。在缺乏干预措施的情况下，约14%的母乳喂养婴儿将通过这一途径获得感染。这种相对较低的传播率令人惊讶，因为婴儿在18个月或更长时间内每天多次摄入含有病毒的母乳。婴儿口腔传播的低效率是有趣的。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子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阻止感染的建立，从而影响传播。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疾病进展缓慢。我们假设人乳寡糖（HMO）、可溶性toll样受体（sTLR）和其他先天免疫因子可能在通过母乳喂养预防HIV的口服传播和调节疾病进展中发挥作用。母乳喂养的婴儿提供了一个独特的人类挑战模型来研究这些新的因素。利用现有的临床样本，从900多名由赞比亚感染艾滋病毒的母亲所生的母乳喂养的婴儿中，我们将表征母乳中HMO、sTLR和其他粘膜免疫成分，并研究它们在婴儿口服艾滋病毒传播中的作用。除了已经收集的临床数据外，我们还将纳入母乳中HIV RNA和DNA脱落的详细病毒学研究。我们已经组建了一个多学科的科学团队，他们在粘膜液的先天免疫方面具有特定的专业知识，结合大型临床数据库和病毒学研究，将允许严格和强大的流行病学分析来调查：(1)母乳中较高浓度的先天免疫因子是否与母乳中HIV-1 RNA和DNA浓度较低的母乳喂养相关的HIV传播率相关，特别是在由于牙齿发育和/或鹅口疮而导致口腔黏膜受损的婴儿中；(2)母乳中的先天免疫因子是否相对于基于外周血HIV RNA和其他母体疾病严重程度指标（包括CD4计数）的预期减少母乳中粘膜病毒的脱落；(3)母乳中较高浓度的先天免疫因子是否与艾滋病毒感染儿童在母乳喂养期间（而非断奶后）疾病进展较慢有关。这些研究将允许对抗HIV先天粘膜免疫的潜在作用进行体内评估，这将为利用粘膜先天免疫的潜在HIV疫苗提供信息。

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.