Identifying key determinants of IgG transplacental transfer from HIV-infected mothers to their fetus

确定 IgG 从 HIV 感染母亲经胎盘转移至胎儿的关键决定因素

• 批准号: 9270942
• 负责人: David R. Martinez
• 金额: $ 3.5万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-01 至 2020-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9270942
• 关键词: Adjuvant; Affect; Affinity; African; Anti-Retroviral Agents; Antibodies; Antigens; Binding; C-Type Lectins; CD4 Positive T Lymphocytes; Cell Count; Cells; Characteristics; Clinical; Communicable Diseases; Coupled; Data; Development; Diarrhea; Disease; Disease Progression; Endothelial Cells; Fc Receptor; Fc domain; Fetus; Fluorescence; Gene Expression; Genes; HIV; HIV Antibodies; HIV Infections; HIV-1; HIV-exposed uninfected infant; Hypergammaglobulinemia; Immunoglobulin G; In Situ; Infant; Infection; Intervention; Life; Logistic Regressions; Maternal Health; Maternal antibody; Measures; Methods; Modeling; Morbidity - disease rate; Mother-to-child HIV transmission; Mothers; Neonatal; Newborn Infant; Outcome; Passive Transfer of Immunity; Pertussis; Phagocytosis; Placenta; Plant Resins; Population; Predisposition; Pregnancy; Prophylactic treatment; Respiratory syncytial virus; Risk; Specificity; Surface; Surface Plasmon Resonance; Syncytiotrophoblast; Therapeutic Intervention; Vaccines; Viral Load result; Woman; Work; antiretroviral therapy; cohort; design; glycosylation; improved; mortality; neonatal Fc receptor; novel; pathogen; placental transfer; pregnant; prevent; receptor; receptor binding; receptor expression; receptor mediated endocytosis; respiratory; therapy design; transmission process

ABSTRACT With an increase in availability and use antiretroviral prophylaxis to prevent mother to child transmission (MTCT) of HIV, the majority of infants born to HIV-infected mothers do not become infected. In fact, more than 1 million HIV exposed uninfected infants (HEU) are born to HIV-infected mothers each year. Interestingly, HEUs are more susceptible to respiratory and diarrheal diseases and have higher morbidity and mortality rates compared to HIV unexposed infants (HU). The mechanism of the increased susceptibility of HEU infants to these fatal infections remains unknown. Previous studies have shown that maternal HIV infection is associated with poor transplacental transfer of IgG antibodies. As maternal antibodies transferred across the placenta to the fetus are critical in protecting infants against disease in the first few months of life, the low levels of maternal antibodies in HEU infants could contribute to their increased risk of acquiring infectious diseases. In preliminary work, I have measured the levels of maternal and infant IgG to a panel of HIV and non-HIV-specific antigens in two large cohorts of clade B and C HIV-infected mother-HEU infant pairs (n = 167). My results indicate that different IgG specificities are not equally transferred to the fetus and that transplacental IgG transfer efficiency varies between mother infant pairs. I hypothesize that placental IgG transfer efficiency in the setting of HIV infection is dependent on maternal HIV-disease progression factors, characteristics of IgG Fc domain, as well as expression of Fc receptors that shuttle IgG across the placenta (i.e., FcRn). Using HIV- infected mothers, I propose to define the impact of maternal HIV-disease progression clinical factors (CD4+ T cell count, viral load, and hypergammaglobulinemia) and IgG characteristics (IgG subclass, Fc receptor binding, and glycosylation signatures) on antigen-specific IgG transplacental transfer efficiency. Furthermore, I will compare expression levels of FcRn, Fcγ receptor, and c-type lectins in placentas from HIV-infected and uninfected mothers to determine if Fc receptor expression predicts IgG transplacental transfer efficiency. Altogether my study will identify key determinants of maternal IgG transplacental transfer in HIV-infected women. These findings will guide the design of interventions to augment the transplacental transfer of antibodies in HEU infants and could inform the development of more effective maternal vaccines to prevent neonatal infections.

抽象的 随着可用性的增加和使用抗逆转录病毒预防措施来预防母婴传播 艾滋病毒母婴传播（MTCT），大多数感染艾滋病毒的母亲所生的婴儿不会被感染。事实上，超过 每年，感染艾滋病毒的母亲会生出 100 万暴露于艾滋病毒的未感染婴儿 (HEU)。有趣的是， HEU 更容易患呼吸道和腹泻疾病，并且发病率和死亡率更高 与未暴露于艾滋病毒的婴儿（HU）相比。 HEU婴儿易感性增加的机制 这些致命的感染仍然未知。此前的研究表明，母亲艾滋病毒感染与 IgG 抗体经胎盘转移较差。当母体抗体穿过胎盘转移到 胎儿对于保护婴儿在生命最初几个月免受疾病至关重要，胎儿的低水平 HEU 婴儿中的母体抗体可能会增加他们感染传染病的风险。在 在前期工作中，我测量了一组 HIV 和非 HIV 特异性人群的母婴 IgG 水平 两组 B 型和 C 型 HIV 感染的母亲 - HEU 婴儿对 (n = 167) 中的抗原。我的结果 表明不同的 IgG 特异性不会同等地转移给胎儿，并且经胎盘 IgG 母婴之间的转移效率各不相同。我假设胎盘 IgG 转移效率 HIV 感染情况取决于母亲 HIV 疾病进展因素、IgG Fc 特征 结构域，以及将 IgG 穿过胎盘的 Fc 受体的表达（即 FcRn）。使用艾滋病毒- 受感染的母亲，我建议定义影响母亲 HIV 疾病进展的临床因素（CD4+ T 细胞计数、病毒载量和高丙种球蛋白血症）和 IgG 特征（IgG 亚类、Fc 受体 结合和糖基化特征）对抗原特异性 IgG 经胎盘转移效率的影响。此外，我 将比较 HIV 感染者胎盘中 FcRn、Fcγ 受体和 c 型凝集素的表达水平 未感染的母亲以确定 Fc 受体表达是否可以预测 IgG 经胎盘转移效率。 总之，我的研究将确定 HIV 感染者母体 IgG 经胎盘转移的关键决定因素 女性。这些发现将指导干预措施的设计，以增强经胎盘转移 HEU 婴儿体内产生抗体，可以为开发更有效的孕产妇疫苗提供信息，以预防 新生儿感染。