The Maternal Immune Legacy of In Utero HIV Exposure

子宫内艾滋病毒暴露的母体免疫遗产

• 批准号: 10312146
• 负责人: Whitney Elizabeth Harrington
• 金额: $ 20.64万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-12-15 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10312146
• 关键词: Activities of Daily Living; Acute; Adult; African; Alleles; Antibodies; Antigens; Birth; Blood Cells; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cells; Cellular Immunity; Characteristics; Common Epitope; Communicable Diseases; Computational algorithm; Cytomegalovirus; Cytomegalovirus Infections; DNA; Data; Development; Disease susceptibility; Exhibits; Exposure to; Fetus; Flow Cytometry; Frequencies; HIV; HIV Infections; HIV-exposed uninfected infant; Heterogeneity; Immune; Immune response; Immune system; Immunity; Immunization; Individual; Infant; Infection; Inherited; Knowledge; Leukocytes; Life; Memory; Microchimerism; Modeling; Outcome; Partner in relationship; Peptides; Peripheral Blood Mononuclear Cell; Phenotype; Placenta; Play; Pregnancy; Pregnant Women; Proliferating; Research; Role; Sampling; Serology; South Africa; Specificity; System; T cell receptor repertoire sequencing; T memory cell; T-Cell Receptor; T-Lymphocyte; T-cell receptor repertoire; Testing; Time; Tumor-infiltrating immune cells; Vaccinated; Vaccination; Viral; Viral Load result; antigen binding; base; cell type; cohort; experience; healthy pregnancy; in utero; infancy; infant infection; novel; offspring; pathogen; prenatal exposure; response; single-cell RNA sequencing

PROJECT SUMMARY Nearly 1.3 million infants who are HIV-exposed but uninfected (iHEU) are born each year. Maternal HIV infection has a profound and long-lasting impact on the cellular immunity of iHEU through as yet unexplained mechanisms. Maternal microchimerism (MMc) refers to the transfer of rare maternal cells to the fetus during pregnancy which may persist for decades after birth. In offspring of healthy pregnancies at birth, these maternal cells are present in many different immune subsets with the highest level in antigen experienced T-cells; however, the impact of these cells on infant immunity is unexplored. Infant T-cell immunity maybe restricted during early life, so inherited maternal cellular immunity may play a crucial role in response to infection in the offspring. In a cohort from South Africa, we have found that MMc is easily detectable in both iHEU and infants unexposed to HIV (iHU) across the first year of life. It is unknown whether the cell type, diversity, or antigen-specificity of these maternal cells varies between iHEU and iHU. Adults living with HIV have an increased CD8 to CD4 T-cell ratio and a markedly restricted T-cell receptor (TCR) repertoire, and we and others have observed CD8 T-cell infiltration into the placentas of pregnant women living with HIV. Based on these observations, we hypothesize that the maternal T-cells acquired by iHEU are shifted toward CD8 T-cells with a restricted TCR repertoire, as compared to those acquired by iHU. Further, we have observed that some iHEU and iHU exhibit a 50-fold increase in MMc at 15 and 36 weeks of life, such that up to 1 in 200 white blood cells appears to be maternal. This expansion provides us an opportunity to evaluate the TCR repertoire under conditions that likely reflect a new immune stimulation. At the time of these expansions the infants are well and have not recently been vaccinated, so these expansions may result from newly acquired infections. For example, more than half of African infants are infected with cytomegalovirus (CMV) in the first six months of life, and infection is often asymptomatic. We expect that the mothers of these infants will be ubiquitously CMV infected, with 10-30% of memory CD8 T-cells CMV-dedicated. We therefore hypothesize that these large increases in MMc reflect maternal CMV-specific T-cells which expand during acute CMV infection in the infant. Using peripheral blood mononuclear cells from the same cohort, we now propose to investigate the distribution and diversity of maternal T-cells acquired by iHEU and iHU. We further propose to investigate the functional capacity of maternal CMV-specific memory T-cells by determining whether they proliferate in response to acute CMV infection in the infant. We anticipate that this study will demonstrate that inherited maternal cellular immunity plays an important role in responding to infection during infancy with a differing effect in iHEU and iHU. Such an observation would have profound implications for the study of infant immunity, vaccination, and infectious disease susceptibility. We propose a novel model in which the immune responses observed during infancy are the product of two, rather than one, immune systems.

项目摘要 每年有近130万婴儿出生时接触艾滋病毒但未受感染。孕产妇艾滋病毒感染 通过尚未解释的机制对iHEU的细胞免疫产生深远而持久的影响。 母体微嵌合体（MMc）是指妊娠期间罕见的母体细胞转移到胎儿， 可能在出生后持续数十年。在出生时健康妊娠的后代中，这些母体细胞存在于 在许多不同的免疫亚群中，具有最高水平的抗原经历的T细胞;然而， 这些细胞对婴儿免疫力的影响还未被探索。婴儿T细胞免疫可能在生命早期受到限制，因此遗传 母体细胞免疫在后代对感染的反应中可能起着至关重要的作用。在南方的一个队列中， 在非洲，我们发现MMc在iHEU和未接触艾滋病毒的婴儿（iHU）中都很容易检测到。 生命的第一年。这些母源性细胞的细胞类型、多样性或抗原特异性是否不同还不清楚 在iHEU和iHU之间。成年艾滋病毒感染者的CD 8/CD 4 T细胞比例增加， 限制性T细胞受体（TCR）库，我们和其他人已经观察到CD 8 T细胞浸润到 感染艾滋病毒的孕妇的胎盘。基于这些观察，我们假设， 通过iHEU获得的T细胞向具有限制性TCR库的CD 8 T细胞转移，与通过iHEU获得的T细胞相比， 被iHU收购。此外，我们已经观察到，一些iHEU和iHU在15 ℃下表现出MMc增加50倍。 和36周的生命，使得高达1/200的白色血细胞似乎是母体的。这种扩展提供了 我们有机会在可能反映新的免疫刺激的条件下评估TCR库。 在这些扩展的时候，婴儿很好，最近没有接种疫苗，所以这些扩展 可能是由于新感染引起的。例如，超过一半的非洲婴儿感染了 巨细胞病毒（CMV）在生命的前六个月，感染往往是无症状的。我们预计 这些婴儿的母亲将普遍感染CMV，其中10-30%的记忆性CD 8 T细胞是CMV专用的。 因此，我们假设MMc的大量增加反映了母体CMV特异性T细胞的扩增， 在婴儿急性CMV感染期间。使用来自同一队列的外周血单核细胞，我们 现在建议研究由iHEU和iHU获得的母体T细胞的分布和多样性。我们 进一步提出通过测定母体CMV特异性记忆T细胞的功能能力， 它们是否在婴儿急性CMV感染后增殖。我们预计，这项研究将 表明遗传性母体细胞免疫在应对感染中起着重要作用， 婴儿期，iHEU和iHU的影响不同。这样的观察将对未来产生深远的影响。 婴儿免疫力、疫苗接种和传染病易感性研究。我们提出了一个新的模型， 在婴儿期观察到的免疫反应是两个而不是一个免疫系统的产物。