IgG is differentially and selectively transferred across the placenta in HIV-infected women. IgG is differentially and selectively transferred across the placenta in HIV-infected women

The transplacental transfer of maternal IgG to the developing fetus is critical for infant protection against infectious pathogens in the first year of life. However, factors that modulate the transplacental transfer efficiency of maternal IgG that could be harnessed for maternal vaccine design remain largely undefined. HIV-infected women have impaired placental IgG transfer, yet the mechanism underlying this impaired transfer is unknown, presenting an opportunity to explore factors that contribute to the efficiency of placental IgG transfer. We measured the transplacental transfer efficiency of maternal HIV and other pathogen-specific IgG in historical U.S. (n=120) and Malawian (n=47) cohorts of HIV-infected mothers and their HIV58 exposed uninfected and HIV-infected infants. We then examined the role of maternal HIV disease progression, infant factors, placental Fc receptor expression, and IgG Fc region subclass and glycan signatures and their association with transplacental transfer efficiency of maternal antigen-specific IgG. We established 3 distinct phenotypes of placental IgG transfer efficiency in HIV-infected women, including: 1) efficient transfer of the majority of antigen-specific IgG populations; 2) generally poor IgG transfer phenotype that was strongly associated with maternal CD4+ T cell counts, hypergammaglobulinemia, and frequently yielded non-protective levels of vaccine-specific IgG; and 3) variable transfer of IgG across distinct antigen specificities. Interestingly, maternal IgG characteristics, such as binding to placentally expressed Fc receptors FcgRIIa and FcgRIIIa, IgG subclass frequency, and Fc region glycan profiles were associated with placental IgG transfer efficiency. These maternal IgG transplacental transfer determinants were distinct among different antigen-specific IgG populations. Our findings suggest that in HIV-infected women, both maternal disease progression and Fc region characteristics modulate the selective placental transfer of distinct IgG subpopulations, with implications for both the health of HIV-exposed uninfected infants and maternal vaccine design. Overall design: Placental biopsy samples from HIV-infected Malawian women were sequenced on a Nextseq500 sequencer (Illumina) using 75bp paired-end reads.

母体免疫球蛋白G（IgG）经胎盘转运至发育中的胎儿，对于婴儿在生命最初一年内抵御传染性病原体至关重要。然而，可用于指导母体疫苗研发、调控母体IgG胎盘转运效率的相关因素，目前仍尚未被充分阐明。HIV感染女性存在胎盘IgG转运受损的情况，但该转运受损的背后机制尚不明确，这为探究影响胎盘IgG转运效率的因素提供了研究契机。我们针对美国（n=120）与马拉维（n=47）的历史性队列开展研究，研究对象为HIV感染母亲及其所生的HIV暴露未感染与HIV感染婴儿，检测了母体HIV特异性及其他病原体特异性IgG的胎盘转运效率。随后我们分析了母体HIV疾病进展状况、婴儿相关因素、胎盘Fc受体表达、IgG Fc区域亚类及聚糖特征，以及上述因素与母体抗原特异性IgG胎盘转运效率的关联。我们在HIV感染女性中确立了3种不同的胎盘IgG转运效率表型，具体如下：1）多数抗原特异性IgG群体均可实现高效转运；2）整体IgG转运能力较差的表型，该表型与母体CD4+T细胞计数、高丙种球蛋白血症密切相关，且常产生无保护效力的疫苗特异性IgG；3）不同抗原特异性IgG的转运效率存在差异。值得关注的是，母体IgG的相关特征——如与胎盘表达的Fc受体FcgRIIa和FcgRIIIa的结合能力、IgG亚类频率及Fc区域聚糖谱——与胎盘IgG转运效率显著相关。这些调控母体IgG经胎盘转运的决定因素，在不同抗原特异性IgG群体中存在显著差异。我们的研究结果表明，在HIV感染女性中，母体疾病进展状况与Fc区域特征均可调控不同IgG亚群的选择性胎盘转运，这一发现对于HIV暴露未感染婴儿的健康及母体疫苗研发均具有重要指导意义。总体研究设计：本研究针对马拉维HIV感染女性的胎盘活检样本，采用Illumina Nextseq500测序仪，以75bp双端测序读段进行测序。