Identification of Protective Innate Immune Memory Responses Against HIV Acquisition in the Human Female Genital Tract

项目总结 全世界妇女感染艾滋病毒的主要途径是性传播。低艾滋病毒感染率 女性的性行为传播率(0.08%)表明当地的先天免疫机制有助于 保护。然而，导致预防或获得女性生殖道艾滋病毒的粘膜事件 (FGT)在很大程度上是未知的。因此，确定预防艾滋病毒感染的早期粘膜机制至关重要。 建立目标细胞，以便为妇女制定有效的预防办法。 训练性免疫是先天免疫细胞在最初的刺激后产生的功能修饰 对异源二次刺激的先天免疫反应增强。它可以由细菌诱导， 真菌和病毒成分通过感染或疫苗接种，并导致持久的表观遗传修饰 在造血祖细胞中。这意味着经过训练的天然细胞可以通过以下方式到达粘膜表面 用来自骨髓的新的训练细胞补充组织驻留细胞或在 暴露于微生物群和粘膜感染。然而，训练有素的免疫对免疫的贡献 包括FGT在内的人体粘膜表面的保护作用是完全未知的。国际和平研究所的研究小组 最近发现，树突状细胞和中性粒细胞在FGT、先天细胞参与HIV的发病机制， 表达转录本并分泌细胞因子和抗菌素，这是训练有素的免疫反应和 具有已知的抗艾滋病毒活性。根据这些初步结果，这里测试的假设是生殖器 树突状细胞和中性粒细胞通过训练有素的先天免疫反应来预防艾滋病毒感染。建议数 该项目建立在PI之前的工作基础上，现在寻求定义生殖器DC和 并确定受过先天训练的免疫力如何有助于妇女的抗艾滋病毒粘膜保护。 单细胞测序方法确定表型、转录和表观遗传学特征 经过训练的DC和中性粒细胞将与体外功能分析相结合，直接确定抗艾滋病毒的活性。 预计这些研究将首次确定FGT中受过训练的免疫细胞如何对 预防感染艾滋病毒。识别一种可诱导/可修改的先天保护形式 FGT中的HIV将代表着我们对HIV感染是如何在 粘膜。同样重要的是，这些发现将产生积极的翻译影响，因为确定 负责抗艾滋病毒保护的靶向细胞和训练有素的免疫机制将作为 基金会制定新的预防策略，防止全球妇女感染艾滋病毒。

PROJECT SUMMARY The main route for HIV acquisition in women of worldwide is sexual transmission. The low rate of HIV transmission per sexual act (0.08%) in women indicates that local innate immune mechanisms contribute to protection. Yet, the mucosal events that lead to the prevention or acquisition of HIV in the female genital tract (FGT) are largely unknown. Thus, it is critical to identify the early mucosal mechanisms that prevent HIV infection of target cells, in order to develop effective preventive approaches for women. Trained immunity is the functional modification of innate immune cells after initial stimulation that generates heightened innate immune responses to heterologous secondary stimulations. It can be induced by bacterial, fungal, and viral components through infection or vaccination, and leads to long-lasting epigenetic modifications in hematopoietic stem cell progenitors. This implies that trained innate cells can reach mucosal surfaces by replenishment of tissue-resident cells with new trained cells from the bone marrow or be generated after exposure to the microbiome and mucosal infections. However, the contribution of trained immunity to immune protection in human mucosal surfaces, including the FGT, is completely unknown. The PI’s research group recently discovered that dendritic cells and neutrophils in the FGT, innate cells involved in HIV pathogenesis, express transcripts and secrete cytokines and antimicrobials characteristic of trained immune responses and with known anti-HIV activity. Based on these preliminary results, the hypothesis being tested here is that genital DCs and neutrophils protect against HIV acquisition through trained innate immune responses. The proposed project builds on the PI’s prior work, and now seeks to define the trained immune signatures of genital DCs and neutrophils and determine how innate trained immunity contributes to anti-HIV mucosal protection of women. Single-cell sequencing approaches to define the phenotypical, transcriptional, and epigenetic signatures of trained DCs and neutrophils will be combined with in vitro functional assays to directly determine anti-HIV activity. It is expected that these studies will define, for the first time, how trained immune cells in the FGT contribute to protection against HIV acquisition. The identification of an inducible/modifiable form of innate protection against HIV in the FGT would represent a breakthrough in our understanding of how HIV acquisition occurs in the mucosa. Equally important, these findings will have a positive translational impact, since the identification of targetable cells and mechanisms of trained immunity responsible for anti-HIV protection will serve as the foundation to develop novel prevention strategies against HIV acquisition in women worldwide.