Immunomodulatory Properties of BCG: Implications for MTCT

描述（由申请方提供）：本提案的目的是检验以下假设：新生儿卡介苗接种导致免疫应答激活，可能增加HIV阳性母亲母乳喂养的婴儿对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，并将使她能够发展以患者为基础的免疫学研究的专业知识。此外，它提供了一个长期寻求的机会，以发展国际研究技能，并促进与拉丁美洲，候选人的原籍地区的学术合作。该提案的具体目的是评估BCG对HIV进入所需的辅助受体（CCR 5和CXCR 4）表达以及单核细胞对HIV感染的易感性的影响。研究的初始阶段将在体外进行，使用来自健康婴儿的脐带血细胞。将使用FACS分析进行共受体水平的测定，并使用表达重组GFP的HIV-1测量单轮HIV感染。本研究的临床阶段将在优化所有相关测定后进行，并将涉及健康新生儿。这一阶段是对卡介苗接种前后单核细胞的共受体表达和HIV易感性的纵向评估。将在BCG接种后6周从相同婴儿获得的脐带血单核细胞（pre-BCG）和外周血单核细胞中测量活化标志物和HIV易感性。在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通过接触母乳而感染的。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往往不安全或不可行。本研究结果将为进一步探讨BCG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免疫学依据。BCG对HIV进入所需的辅助受体的作用可能对HIV暴露的母乳喂养的新生儿接种BCG疫苗的时机产生影响。

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.