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

马拉维子宫内 HIV 暴露对婴儿 T 和 B 细胞反应的影响

基本信息

批准号：
10165763
负责人：
Cristiana Cairo
金额：
$ 43.3万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-06-07 至 2023-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10165763
关键词：
Adopted Affect Africa South of the Sahara African Age-Months Antigen-Antibody Complex Antigens B-Lymphocyte Subsets B-Lymphocytes BCG Live Birth Breast Feeding Cell Compartmentation Cells Child Childhood Clinic Clinical Research Conceptions Conflict (Psychology)Country Cytometry Development Diagnosis Effectiveness Enrollment Exposure to Female of child bearing age Flow Cytometry HIV HIV Infections HIV Seronegativity HIV diagnosis HIV-exposed uninfected infant Health Health Policy Human immunodeficiency virus test Immune Immune system Immunity Immunization Immunoglobulin Class Switching Immunoglobulin Somatic Hypermutation Immunoglobulin Switch Recombination Immunologics Immunologist Immunology Immunology procedure Impact evaluation Infant Infant Health Infection Infrastructure Knowledge Life Malawi Measures Morbidity - disease rate Mothers Neonatal Participant Pathway interactions Phenotype Population Pregnancy Pregnant Women Prevention Process Production Proteins Public Health Regimen Reporting Research Research Design Respiratory Tract Infections Rest Specimen Stimulus T cell response T-Cell Activation T-Lymphocyte Technology Testing Tetanus Toxoid Third Pregnancy Trimester Time Umbilical Cord Blood Vaccine Antigen Vertical Disease Transmission Viral Load result Viremia Visit Vulnerable Populations Woman adaptive immune response antenatal antenatal care antigen-specific T cells antiretroviral therapy clinical risk cohort congenital infection cytokine disorder risk enteric infection experience follow-up in utero infancy longitudinal analysis mortality peripheral blood prenatal prenatal exposure preservation prevent programs response success tuberculin purified protein derivative

项目摘要

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.

项目概要每年有超过 150 万婴儿出生时就在子宫内暴露于 HIV 感染。在预防的同时母婴传播成功预防先天性感染、HIV暴露但未感染的婴儿 (HEU) 比未暴露的同类更容易受到常见的肠道和呼吸道感染，并且死亡率较高。导致这种现象的精确免疫学改变 HEU 婴儿之间的差异从未得到明确的描述。在广泛使用后进行的研究抗逆转录病毒治疗（ART）显示艾滋病毒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。我们认为，与子宫内艾滋病毒相关的免疫紊乱有效的抗逆转录病毒治疗可以减少暴露，并且妊娠期间艾滋病毒感染的控制时间越长，婴儿经历的免疫改变和临床疾病风险较小。在本研究中，我们将测试假设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当婴儿暴露于高水平的艾滋病毒感染时，免疫反应与未暴露于艾滋病毒的婴儿相似在怀孕的大部分时间里，适应性免疫反应都会失调。我们提出纵向对 HEU 婴儿的适应性免疫子集进行分析，比较三个特征良好的母婴队列与撒哈拉以南非洲的大部分地区一样，马拉维的妇女经常在马拉维的一个医疗中心接受第一次治疗。当她们在怀孕后期接受产前护理时，即可诊断出艾滋病毒。在这种情况下，我们将招收 (1) 名婴儿妊娠 26 周后第一次产前检查时被诊断为 HIV 感染的妇女所生的孩子，因此暴露超过一半的妊娠期病毒血症不受控制，(2) 接受抗逆转录病毒治疗的妇女所生的婴儿病毒检测不到 (3) 未感染艾滋病毒的母亲所生的未暴露于艾滋病毒的婴儿。所有艾滋病毒感染者女性将接受相同的 ART 治疗方案，并在 9 个月的随访期间母乳喂养婴儿时期。我们将通过检测出生时、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、激活水平以及抗原特异性 T 和 B 细胞针对三组婴儿的反应，应用最先进的技术进行详细而全面的反应分析。这将是对艾滋病毒暴露对人类健康影响的最全面的纵向评估。婴儿适应性免疫反应的发展。研究结果将为公共卫生政策有助于确定 ART 治疗的最佳时机，以最大限度地提高婴儿健康和生存。