Immunomodulatory Properties of BCG: Implications for MTCT

描述(申请人提供)：这项建议的目的是测试一种假设，即新生儿接种卡介苗会激活免疫反应，从而可能增加艾滋病毒阳性母亲的母乳喂养婴儿感染艾滋病毒的易感性。这项研究源于候选人在异源免疫方面的博士后研究，并将使她在以患者为基础的免疫学研究方面发展专业知识。此外，它还提供了一个长期寻求的机会，以发展国际研究技能，并促进与候选人原籍地区拉丁美洲的学术合作。这项建议的具体目的是评估卡介苗对HIV进入所需的辅助受体(CCR5和CXCR4)表达的影响，以及对单个核细胞对HIV感染的易感性的影响。这项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。共受体水平的测定将使用FACS分析进行，单轮艾滋病毒感染将使用表达GFP的重组HIV-1进行测量。这项研究的临床阶段将在所有涉及的分析方法优化后进行，并将涉及健康的新生儿。这一阶段是对卡介苗接种前后单核细胞共受体表达和HIV易感性的纵向评估。卡介苗接种后6周采集脐血单个核细胞(Pre-BCG)和外周血单个核细胞(PBMC)，检测活化标志物和HIV易感性。通过母婴传播感染艾滋病毒的婴儿中，有很大一部分是在产后时期通过接触母乳感染的。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，这一选择对低收入环境中的妇女来说往往是不安全或不可行的。本研究结果将为进一步探讨卡介苗诱导的免疫激活对宿主对HIV易感性的临床作用提供概念性的免疫学基础。卡介苗对艾滋病毒进入所需的辅助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间有影响。

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.