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

摘要 随着抗逆转录病毒预防的提供和使用的增加， 在艾滋病毒的母婴传播（MTCT）中，感染艾滋病毒的母亲所生的大多数婴儿没有受到感染。事实上， 每年有100万未感染艾滋病毒的婴儿由感染艾滋病毒的母亲所生。有趣的是， 高浓缩铀更容易患上呼吸道和消化道疾病，发病率和死亡率也更高 与未接触艾滋病毒的婴儿（HU）相比。高浓铀患儿对高浓铀易感性增加的机制 这些致命的感染仍然未知。以前的研究表明，孕产妇艾滋病毒感染与 IgG抗体经胎盘转移不良。当母体抗体通过胎盘转移到 胎儿在生命的最初几个月内对保护婴儿免受疾病的影响至关重要， 高浓缩铀婴儿体内的母体抗体可能会增加他们感染传染病的风险。在 初步工作，我已经测量了孕产妇和婴儿的IgG水平，以一个小组的艾滋病毒和非艾滋病毒特异性 在两个大的进化枝B和C的HIV感染的母亲-高浓缩铀婴儿对（n = 167）的队列中检测抗原。我的结果 表明不同的IgG特异性不能同等地转移到胎儿， 母婴之间的传递效率不同。我假设胎盘IgG的转移效率， HIV感染的发生取决于母体HIV疾病进展因素、IgG Fc的特征 结构域，以及Fc受体的表达，所述Fc受体使IgG穿梭穿过胎盘（即，FcRn）。使用艾滋病毒- 感染的母亲，我建议定义产妇艾滋病毒疾病进展的临床因素（CD 4 + 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 结合和糖基化标记）对抗原特异性IgG经胎盘转移效率的影响。而且我 将比较HIV感染者和未感染者胎盘中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。 妇女这些发现将指导干预措施的设计，以增加经胎盘转移， 这可能有助于开发更有效的孕产妇疫苗， 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.