Oral Transmission of HIV through Breastfeeding

通过母乳喂养经口传播艾滋病毒

• 批准号: 8270323
• 负责人: Grace M Aldrovandi
• 金额: $ 35.57万
• 依托单位: COLUMBIA UNIVERSITY HEALTH SCIENCES
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8270323
• 关键词: Accounting; Affect; Binding; Birth; Blood; Breast Feeding; CCL3 gene; CD14 gene; CD209 gene; CD4 Lymphocyte Count; Child; Clinical; Clinical Data; Clinical Trials; Complement; Complex; DNA; Databases; Development; Diarrhea; Disease; Disease Progression; Dose; Epidemiology; Epithelial; Evaluation; HIV; HIV Infections; HIV vaccine; HIV-1; Human; Human Milk; Immune; Immunologic Tests; In Vitro; Infant; Infection; Inflammation; Intention; Interleukin-15; Interleukin-7; Interleukin-8; Intervention; Investigation; Kenya; Lactoferrin; Leukocytes; Liquid substance; Logistics; Mammary gland; Measures; Milk; Modeling; Morbidity - disease rate; Mothers; Mucosal Immunity; Natural Immunity; Neonatal; Nevirapine; Oligosaccharides; Oral; Oral candidiasis; Oral cavity; Oral mucous membrane structure; PI3 gene; Pathway interactions; Peptide Hydrolases; Phacochoerus aethiopicus Elafin protein; Play; Postpartum Period; Pregnancy; Pregnant Women; Prevention; Process; Prophylactic treatment; Public Health; RANTES; RNA; Recruitment Activity; Relative (related person); Research Design; Resistance; Risk; Role; Route; SLPI gene; Sampling; Severities; Severity of illness; Surface; Teething; Testing; Time; Toll-Like Receptor 2; Toll-like receptors; Tooth structure; Vaccines; Vagina; Vertical Disease Transmission; Virus; Virus Shedding; Visit; Weaning; Woman; Zambia; antiretroviral therapy; base; chemokine; cohort; in vivo; intrapartum; neonate; novel; oral HIV; peripheral blood; postnatal; prevent; prophylactic; public health relevance; sex; transmission process

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.

描述（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。如果不采取干预措施，大约 14% 的母乳喂养婴儿会通过这种途径感染。这种相对较低的传播率令人惊讶，因为婴儿在 18 个月或更长的时间内每天多次摄入含有病毒的母乳。婴儿的口腔传播效率低下是很有趣的。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防止感染的建立来影响传播。这些因素还可能减少激活，从而减缓感染艾滋病毒的母乳喂养婴儿的疾病进展。我们假设母乳寡糖 (HMO)、可溶性 Toll 样受体 (sTLR) 和其他先天免疫因子可能在预防通过母乳喂养经口传播艾滋病毒和调节疾病进展方面发挥作用。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因素。利用来自赞比亚感染 HIV 的母亲所生的 900 多名母乳喂养婴儿的现有临床样本，我们将描述母乳中 HMO、sTLR 和其他粘膜免疫成分的特征，并研究它们在婴儿经口 HIV 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。我们组建了一支多学科科学团队，他们在粘膜液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，将允许进行严格而有力的流行病学分析来调查：（1）是否较高浓度的先天免疫母乳中的因素与母乳喂养相关的艾滋病毒传播率较低有关，与母乳中的 HIV-1 RNA 和 DNA 浓度无关，尤其是在因牙齿发育和/或鹅口疮而口腔粘膜受损的婴儿中； (2) 母乳中的先天免疫因素是否会减少母乳中粘膜病毒的排出，相对于基于外周血中 HIV RNA 和其他孕产妇疾病严重程度标记（包括 CD4 计数）的预期排出量； (3) 母乳中较高浓度的先天免疫因子是否与 HIV 感染儿童在母乳喂养期间而非断奶后疾病进展较慢有关。这些研究将能够对抗艾滋病毒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艾滋病毒疫苗提供信息。 公共健康相关性：我们建议表征先天免疫的新成分，包括母乳寡糖、可溶性 Toll 样受体以及来自 HIV 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母乳喂养经口传播、预防粘膜病毒脱落和延缓受感染母乳喂养婴儿疾病进展方面的作用。