Immunomodulatory Properties of BCG: Implications for MTCT

描述（由申请人提供）：本提案的目的是验证新生儿接种卡介苗导致免疫反应激活的假设，该免疫反应可能增加HIV阳性母亲的母乳喂养婴儿对HIV感染的易感性。这项调查源于候选人作为异源免疫博士后研究员的研究，并将使她在基于患者的免疫学研究方面发展专业知识。此外，它提供了一个长期寻求的机会来发展国际研究技能，并促进与候选人原籍地区拉丁美洲的学术合作。本研究的具体目的是评估卡介苗对HIV进入所需共受体（CCR5和CXCR4）表达的影响以及对单核细胞对HIV感染易感性的影响。该研究的初始阶段将在体外进行，使用健康婴儿的脐带血细胞。用FACS分析测定共受体水平，用表达重组gfp的HIV-1检测单轮HIV感染。该研究的临床阶段将在优化所有涉及的检测后进行，并将涉及健康的新生儿。这一阶段是对卡介苗接种前后单个核细胞共受体表达和HIV易感性的纵向评估。将在接种卡介苗后6周获得的同一婴儿的脐带血单个核细胞（卡介苗前）和外周血单个核细胞中测量激活标记物和HIV易感性。通过母婴传播感染艾滋病毒的婴儿中，很大一部分是在产后期间因接触母乳而感染的。虽然完全替代喂养消除了通过哺乳感染艾滋病毒的风险，但由于耻辱、配方奶粉成本高或难以获得饮用水，这种选择对低收入环境中的妇女来说往往不安全或不可行。本研究结果将为进一步探索bcg诱导的免疫激活对宿主HIV易感性的临床作用提供概念免疫学基础。卡介苗对艾滋病毒进入所需的共受体的影响可能对暴露于艾滋病毒的母乳喂养新生儿接种卡介苗的时机有影响。

DESCRIPTION (provided by applicant): The purpose of this proposal is to test the hypothesis that neonatal BCG vaccination leads to activation of immune response that may increase the susceptibility to HIV infection in breast-fed infants of HIV-positive mothers. This investigation stems from the candidate's research as a post-doctoral fellow in heterologous ^ immunity and will allow her to develop expertise in patient-based immunology research. Furthermore, it provides a long-sought opportunity to develop skills in international research and foster an academic collaboration with Latin America, the candidate's region of origin. The specific aim of this proposal is to evaluate the effect of BCG on expression of co-receptors required for HIV entry (CCR5 and CXCR4) and on susceptibility of mononuclear cells to HIV infection. The initial phase of the study will be performed in vitro, using cord blood cells from healthy infants. Determination of co- receptors levels will be performed using FACS analysis and single-round HIV infection will be measured with a recombinant GFP-expressing HIV-1. The clinical phase of the study will proceed after optimization of all assays involved, and will involve healthy neonates. This phase is a longitudinal assessment of co-receptor expression and HIV susceptibility of mononuclear cells before and after BCG vaccination. Activation markers and HIV susceptibility will be measured in cord blood mononuclear cells (pre-BCG) and peripheral blood mononuclear cells obtained from the same infants 6 weeks'after BCG vaccination. A significant proportion of infants infected with HIV through maternal-to-child-transmission (MTCT) are infected in the post-partum period through exposure to breastmilk. Although exclusive replacement feeding eliminates the risk of HIV acquisition through lactation, this option is often not safe or feasible for women in lower income settings due to stigma, high cost of formula, or poor access to potable water. The results from this study will provide a conceptual immunologic basis for further exploring the clinical effect of BCG-induced immune activation on host susceptibility to HIV. The effect of BCG on co-receptors required for HIV entry may have implications regarding the timing of BCG vaccination in HIV-exposed breastfed neonates.