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

项目摘要 每年有150多万婴儿出生时在子宫内感染艾滋病毒。虽然预防 母婴传播成功地预防了先天性感染，艾滋病毒暴露但未感染的婴儿 (HEU)比未接触的人更容易感染肠道和呼吸道感染， 死亡率也更高。造成这种现象的精确的免疫学改变 在高浓缩铀婴儿中，从来没有明确的特征。在广泛获得 抗逆转录病毒治疗（ART）显示，艾滋病毒感染者和非感染者之间的发病率和死亡率差异不太明显。 暴露和未暴露的婴儿。我们相信子宫内感染艾滋病毒的免疫紊乱 有效的抗逆转录病毒疗法可以减轻暴露，妊娠期控制艾滋病毒感染的时间越长， 婴儿将经历的免疫改变和疾病的临床风险更少。在这项研究中，我们将测试 一种假设认为，自受孕以来艾滋病毒感染受到抑制的母亲所生的婴儿将具有适应性， 免疫应答与未暴露于HIV的婴儿相似，而暴露于高水平HIV感染的婴儿 在怀孕的大部分时间里，都会有一个失调的适应性免疫反应。我们提出了一个纵向的 HEU婴儿的适应性免疫亚群分析，比较三个特征良好的母婴队列 在马拉维，和撒哈拉以南非洲的大部分地区一样， 在怀孕后期接受产前护理时，可诊断出艾滋病毒。在这种情况下，我们将招募（1）婴儿 怀孕26周后首次产前检查时被诊断感染艾滋病毒的妇女所生， 超过一半的妊娠期不受控制的病毒血症，（2）接受ART的妇女所生的婴儿， （3）未感染HIV的母亲所生的未暴露于HIV的婴儿。所有感染艾滋病毒的 妇女将接受相同的抗逆转录病毒疗法，并在9个月的随访期间母乳喂养婴儿 期我们将通过探测出生时、4个月和9个月时的免疫系统来评估适应性免疫反应 年龄与多克隆刺激和常规免疫抗原，所有婴儿将暴露于 生命的前三个月我们将比较分化，活化水平和抗原特异性T和B细胞 三组婴儿的反应，应用最先进的技术，详细和全面的 分析。这将是对艾滋病毒暴露对艾滋病毒感染者的影响进行的最全面的纵向评估。 婴儿适应性免疫反应的发展。这一结果将为 公共卫生政策，帮助确定ART治疗的最佳时机，以最大限度地提高婴儿健康， 生存

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.