The impact of in utero HIV exposure on infant T and B cell responses in Malawi

项目摘要 每年有150多万婴儿出生时就暴露在子宫内感染艾滋病毒。同时防止 母婴传播成功预防先天性感染，接触艾滋病毒但未感染的婴儿 (HEU)比未接触HEU的人更容易感染常见的肠道和呼吸道感染， 并且有更高的死亡率。导致这一现象的确切的免疫变化 HEU中的婴儿从未被明确描述过。在广泛获得后进行的研究 抗逆转录病毒疗法(ART)显示，HIV与HIV在发病率和死亡率方面的差异不那么明显 接触过和未接触过的婴儿。我们认为与子宫内艾滋病毒相关的免疫紊乱 通过有效的抗逆转录病毒疗法可以减少接触，在怀孕期间控制艾滋病毒感染的时间越长， 较少的免疫变化和婴儿将经历的疾病的临床风险。在这项研究中，我们将测试 自怀孕以来HIV感染被抑制的母亲所生婴儿将具有适应性的假说 与未接触艾滋病毒的婴儿在暴露于高水平艾滋病毒感染时的免疫反应相似 在怀孕的大部分时间里都会有一种失调的适应性免疫反应。我们提出了一个纵向的 HEU婴儿获得性免疫亚群分析--三个典型母婴队列的比较 来自马拉维的一家保健中心，在那里，就像在撒哈拉以南非洲的大部分地区一样，妇女经常接受第一次 当他们在怀孕后期提供产前护理时，就可以进行艾滋病毒诊断。在此设置中，我们将招收(1)名婴儿 在怀孕26周后首次产前检查时被诊断为艾滋病毒感染的妇女所生的孩子，从而暴露在 超过一半的孕妇有无法控制的病毒血症，(2)接受抗逆转录病毒治疗的妇女所生的婴儿感染了无法检测到的病毒 怀孕前的负荷，以及(3)未感染艾滋病毒的母亲所生的未接触艾滋病毒的婴儿。所有感染艾滋病毒的人 妇女将接受同样的抗逆转录病毒治疗，并将在9个月的随访期间母乳喂养她们的婴儿。 句号。我们将通过在出生时、4个月和9个月时探测免疫系统来评估适应性免疫反应。 同时使用多克隆刺激和常规免疫抗原的年龄，所有婴儿都将在 生命的前三个月。我们将比较分化、激活水平和抗原特异性T细胞和B细胞 针对三组婴儿的回应，应用最先进的技术进行详细和全面的 分析。这将是对艾滋病毒暴露对人类健康影响最全面的纵向评估 婴儿获得性免疫反应的发展。这一结果将为以下方面提供重要证据 公共卫生政策，帮助确定抗逆转录病毒治疗的最佳时机，以最大限度地提高婴儿健康和 生死存亡。

Project Summary More than 1.5 million infants each year are born with in utero exposure to HIV infection. While prevention of mother to child transmission successfully prevents congenital infection, HIV exposed but uninfected infants (HEU) are more susceptible to common enteric and respiratory infections than their unexposed counterparts, and have higher mortality rate. The precise immunologic alterations that are responsible for this phenomenon among HEU infants have never been clearly characterized. Studies conducted after widespread availability of antiretroviral therapy (ART) have shown less pronounced differences in morbidity and mortality between HIV exposed and unexposed infants. We believe that the immune perturbations associated with in utero HIV exposure are mitigated by effective ART and the longer the control of the HIV infection is during gestation, the less immune alterations and clinical risk of disease the infant will experience. In this study, we will test the hypothesis that infants born to mothers with suppressed HIV infection since conception will have adaptive immune responses similar to HIV-unexposed infants while infants exposed to high level of HIV infection through most of pregnancy will have a dysregulated adaptive immune response. We propose a longitudinal analysis of adaptive immune subsets in HEU infants, comparing three well-characterized mother-infant cohorts from a single health center in Malawi, where, as in much of sub-Saharan Africa, women often receive their first HIV diagnosis when they present for antenatal care late in pregnancy. In this setting, we will enroll (1) infants born to women diagnosed with HIV infection at the first antenatal visit after 26 weeks gestation, thus exposed to uncontrolled viremia for over half of the pregnancy, (2) infants born to women on ART with undetectable viral loads before conception, and (3) HIV unexposed infants born to HIV uninfected mothers. All HIV-infected women will receive the same ART regimen and will breastfeed their infants during the 9-month follow up period. We will assess the adaptive immune response by probing the immune system at birth, 4 and 9 months of age with both polyclonal stimuli and routine immunization antigens, to which all infants will be exposed in the first three months of life. We will compare differentiation, activation levels and antigen specific T and B cell responses for the three groups of infants, applying state-of-the-art technology for detailed and comprehensive analyses. This will be the most comprehensive longitudinal assessment of the impact of HIV exposure on the development of the adaptive immune responses in infants. The results will provide important evidence for public health policy in helping to determine the optimal timing of ART treatment to maximize infant health and survival.