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

摘要 随着可获得性的增加和使用抗逆转录病毒预防措施来防止母婴传播 在艾滋病毒母婴传播方面，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，不仅仅是 每年有100万感染艾滋病毒的母亲所生的未感染艾滋病毒的婴儿(HEU)。有趣的是， Heus更容易患呼吸道和腹泻疾病，发病率和死亡率更高 与未接触艾滋病毒的婴儿(HU)相比。新生儿HEU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，母体感染艾滋病毒与 免疫球蛋白抗体经胎盘转移不良。当母体抗体通过胎盘转移到 胎儿对于保护婴儿在生命的最初几个月免受疾病的侵袭是至关重要的，低水平的 HEU婴儿的母体抗体可能会增加他们感染传染病的风险。在……里面 前期工作中，我曾测量过母婴免疫球蛋白的水平，以小组的HIV和非HIV特异性 B和C型HIV感染母亲-HEU婴儿对(n=167)的两大队列中的抗原。我的结果 表明不同的免疫球蛋白特异性并不等同地转移到胎儿和经胎盘的免疫球蛋白 母婴对之间的转移效率不同。我假设胎盘中的免疫球蛋白转移效率 HIV感染的环境取决于母亲的HIV-疾病进展因素、Ig G Fc的特性 FcRN结构域，以及运送免疫球蛋白穿过胎盘的Fc受体(FcRN)的表达。使用艾滋病毒- 感染母亲，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)和免疫球蛋白特征(免疫球蛋白亚类、Fc受体 结合和糖基化签名)对抗原特异性免疫球蛋白经胎盘转移效率的影响。此外，我 将比较FcRN、Fcγ受体和C型凝集素在感染艾滋病毒的胎盘中的表达水平 以确定Fc受体的表达是否能预测免疫球蛋白经胎盘的转移效率。 总之，我的研究将确定艾滋病毒感染者母体免疫球蛋白经胎盘转移的关键决定因素 女人。这些发现将指导干预措施的设计，以增强经胎盘转移 HEU婴儿中的抗体，并可为开发更有效的母体疫苗提供信息，以防止 新生儿感染。

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.