Immune correlates of protection against nonprimary congenital cytomegalovirus transmission in an HIV-infected mother-infant cohort

HIV感染母婴群体中预防非原发性先天性巨细胞病毒传播的免疫相关性

• 批准号: 10382241
• 负责人: Jennifer Jenks
• 金额: $ 2.34万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-11-01 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10382241
• 关键词: Academy; Address; Affect; Antibodies; Antibody Response; Antigens; Automobile Driving; Binding; Biological Assay; Brain Injuries; CD4 Positive T Lymphocytes; CMV glycoprotein B; Cells; Child; Chronic; Clinical Trials; Country; Cytomegalovirus; Cytomegalovirus Infections; Cytomegalovirus Vaccines; Developmental Delay Disorders; Epithelial Cells; Epitopes; Face; Flow Cytometry; Glycoproteins; Goals; HIV; HIV Seropositivity; HIV-exposed uninfected infant; Immune; Immune response; Immunity; Immunocompetent; Immunoglobulin G; Immunologics; Impairment; Incidence; Infant; Intellectual functioning disability; Investigation; Knowledge; Maps; Maternal antibody; Maternal-Fetal Transmission; Maternally-Acquired Immunity; Measures; Medicine; Mothers; Natural Immunity; Natural Killer Cells; Nucleotides; Peripheral Blood Mononuclear Cell; Phenotype; Plasma; Play; Population; Pregnant Women; Property; Risk; Role; Sampling Studies; Surface; T cell response; T-Lymphocyte; Vaccine Design; Vaccines; Variant; Vertical Disease Transmission; Viral; Virus; Woman; Work; antigen-specific T cells; cohort; congenital cytomegalovirus; congenital infection; deafness; hearing impairment; immune function; immunogenic; improved; in utero; insight; maternal vaccination; nervous system disorder; neutralizing antibody; next generation; novel; permanent hearing loss; pressure; prevent; response; seropositive; transmission process; vaccine development; vaccine efficacy; γδ T cells

Immune correlates of protection against nonprimary congenital cytomegalovirus transmission in an HIV-infected mother-infant cohort ABSTRACT Vertical transmission of cytomegalovirus (CMV) is the most common congenital infection worldwide, resulting in deafness and neurodevelopmental delay for affected children. Natural maternal immunity to CMV only partially protects against mother-to-child in utero transmission, and indeed, the majority of congenital CMV (cCMV) transmissions worldwide occur in the setting of preexisting maternal immunity. A vaccine to prevent pregnant women from acquiring CMV or subsequently transmitting the virus to their child in utero has been a top priority for the U.S. National Academy of Medicine for nearly twenty years. However, vaccine development remains impeded by a gap in knowledge of the immune responses that protect again cCMV transmission, particularly in CMV-seropositive women. Chronically CMV-infected, HIV-uninfected mothers transmit CMV in utero at a rate of ~1%, yet CMV/HIV- coinfected mothers transmit CMV at a rate 5- to 10-fold higher. The mechanisms underlying this high incidence of cCMV in HIV-infected women remain underexplored but suggest that impaired CMV-specific maternal immunity may contribute to cCMV transmission. Thus, the high incidence of cCMV among HIV-exposed, uninfected infants provides a unique opportunity to define the maternal immune correlates of protection against cCMV transmission in CMV-seropositive populations. In this study, I propose to study samples from 9 historical cohorts spanning 12 countries of HIV-infected mothers and their HIV-exposed infants to define the maternal CMV-specific humoral and cellular responses associated with protection against cCMV. I hypothesize that the high rate of cCMV transmission in chronically HIV/CMV-infected women is due to reduced maternal immune responses against diverse CMV strains compared to HIV-uninfected women. In this study, I aim to (1) Identify the maternal antibody immune correlates of protection against cCMV in HIV/CMV-coinfected mothers, (2) Identify the maternal cellular immune correlates of protection against cCMV in HIV/CMV-coinfected mothers, (3) Compare the diversity of placentally transmitted CMV variants in HIV-exposed and unexposed infants. By identifying maternal immune correlates of protection against cCMV transmission in CMV-seropositive mothers, this work will provide valuable insight into rational vaccine design for CMV-seropositive populations to reduce the global burden of cCMV.

预防非原发先天性巨细胞病毒传播的免疫相关因素 感染艾滋病毒的母婴队列 摘要 巨细胞病毒(CMV)垂直传播是全球最常见的先天性感染，导致 在受影响儿童的耳聋和神经发育延迟方面。仅母体对CMV的天然免疫力 部分预防母婴宫内传播，事实上，大多数先天性巨细胞病毒 全球范围内的传播是在先前存在的母体免疫的情况下发生的。预防的疫苗 孕妇感染CMV或随后将病毒传播给她们的孩子一直是一种 美国国家医学科学院近二十年来的首要任务。然而，疫苗的开发 仍然受阻于对再次保护CCMV传播的免疫反应的了解差距， 尤其是在巨细胞病毒血清阳性的妇女中。 长期感染CMV的母亲和未感染HIV的母亲在宫内传播CMV的比率约为1%，而CMV/HIV- 合并感染的母亲传播巨细胞病毒的比率要高出5到10倍。这种高发病率背后的机制 HIV感染妇女的CCMV仍未被研究，但提示受损的CMV特异性母体 免疫可能参与了CCMV的传播。因此，在接触艾滋病毒的人群中CCMV的高发病率， 未感染的婴儿提供了一个独特的机会来确定母体免疫相关的保护措施 巨细胞病毒血清阳性人群中CCMV的传播。 在这项研究中，我建议研究来自12个国家艾滋病毒感染者的9个历史队列的样本。 母亲及其感染艾滋病毒的婴儿确定母亲巨细胞病毒特异性体液和细胞反应 与针对CCMV的保护相关。我假设CCMV的高传播率是慢性的 感染艾滋病毒/巨细胞病毒的妇女是由于母亲对各种巨细胞病毒毒株的免疫反应减弱所致 与未感染艾滋病毒的女性相比。在这项研究中，我的目标是(1)确定母体抗体与免疫相关 HIV/CMV混合感染母亲对CCMV的保护作用，(2)确定母亲的细胞免疫 HIV/CMV合并感染母亲预防CCMV感染的相关因素(3)胎位差异比较 接触和未接触艾滋病毒的婴儿中传播的巨细胞病毒变异。通过确定母体免疫相关的 在巨细胞病毒血清阳性母亲中预防CCMV传播，这项工作将为 为CMV血清阳性人群设计合理的疫苗，以减轻全球CCMV的负担。