Mechanisms by which trophoblasts recruit T cells to the placental villi during maternal HIV and CMV co-infection

项目摘要 一项新的证据表明，人类的发病率和死亡率正在增加 免疫缺陷病毒(HIV)暴露的未感染婴儿(HEU)与未感染HIV的婴儿的比较 女性(HUU)。随着高浓缩铀儿童人口以每年100万英镑的速度增长，确定了可修改的机制 在这些差异的背后是一个全球卫生优先事项。几项研究表明，在怀孕期间 合并母体HIV感染，暴露于共病原体诱导胎盘免疫激活，这 可能会改变胎盘信号，影响胎儿免疫力。其中一种混合感染是人类巨细胞病毒。 (巨细胞病毒)。流行病学研究表明，人巨细胞病毒混合感染可能与HIV疾病有关。 进展和死亡率增加。最近，我们发现人胎盘绒毛中存在CD8+T细胞。 与来自南非的胎盘相比，怀孕、感染艾滋病毒(PWLHIV)和巨细胞病毒感染的南非妇女 人巨细胞病毒阳性的未感染HIV的妇女。我们假设有招募和移民 母体来源的巨细胞病毒特异性CD8+T细胞从子宫蜕膜到胎盘绒毛。我们假设 滋养层细胞促进抗原特异性CD8+T细胞向胎儿绒毛室迁移， 这进一步加剧了炎症级联，促进了滋养层细胞的凋亡。在……里面 为了验证我们的假设，我们将招募孕妇参加南部开普敦的产前护理 非洲被分成两组：1)艾滋病毒/巨细胞病毒合并感染的孕妇；2)仅感染巨细胞病毒的妇女。 我们将确定这些浸润性T细胞的来源、表型和表位特异性，并检查 滋养层细胞在将这些T细胞招募到绒毛间隙中的作用。拟议的研究将提供一个 对母亲孕期HIV/HCMV混合感染的体内影响的更深层次的概念理解 胎盘免疫力。这些研究可以促进免疫调节和抗病毒药物的发展。 分别针对炎症和巨细胞病毒的治疗可能改善HEU婴儿的临床结局 来自艾滋病毒和巨细胞病毒共同感染的孕妇。

PROJECT ABSTRACT An emerging body of evidence suggests there is increased morbidity and mortality among human immunodeficiency virus (HIV)-exposed uninfected infants (HEUs) compared to infants born to HIV-uninfected women (HUU). With the HEU child population increasing at >1 million/year, identifying modifiable mechanisms underlying these disparities is a global health priority. Several studies suggest that during pregnancy complicated by maternal HIV infection, exposure to co-pathogens induces placental immune activation, which may alter placental signaling affecting fetal immunity. One such co-infection is human cytomegalovirus (HCMV). Epidemiologic studies have reported that HCMV co-infection may contribute to HIV disease progression and increased mortality. We recently identified the presence of CD8+ T cells in placental villi from pregnant, South African women living with HIV (PWLHIV) and HCMV co-infection, compared to placentae from HIV-uninfected women who were HCMV positive. We hypothesize that there is recruitment and migration of maternally-derived HCMV-specific CD8+ T cells from the uterine decidua to placental villi. We posit that trophoblasts promote migration of antigen-specific CD8+ T cells into the fetal villi compartment, which further exacerbates the inflammatory cascade and promotes apoptosis of trophoblast cells. In order to validate our hypothesis, we will enroll pregnant women attending prenatal care in Cape Town, South Africa, into two groups: 1) HIV/HCMV co-infected pregnant women; and 2) women with HCMV infection only. We will determine the origin, phenotype and epitope specificity of these infiltrating T cells, as well as examine the role of trophoblasts in recruiting these T cells into the villous space. The proposed studies will provide a deeper conceptual understanding of the in vivo effects of maternal HIV/HCMV co-infection during pregnancy on placental immunity. These studies could facilitate the development of immunomodulatory and antiviral therapies targeting inflammation and HCMV, respectively, which may improve clinical outcomes in HEU infants from HIV- and HCMV-coinfected pregnant women.