Dichotomy of HIV-Sugar with Vaginal Microbes

项目总结 这一提议是建立在皮马克实验室的一项新发现基础上的，该发现表明，一种“非静电， 特定的、可操纵的糖类‘是HIV的一个依附因素。这种相互作用发生在HIV病毒 低聚甘露糖和细胞N-乙酰氨基葡萄糖(GlcNAc)在受体结合之前。这个 跨生命和非生物(病毒)领域的葡聚糖生物保护导致了我们目前的建议 为了研究这种寡聚体-GlcNAc(或基于寡聚体的)相互作用是否可能支撑一些动态- (I)阴道微生物；(Ii)艾滋病毒；(Iii)它们的人类宿主之间的相互作用。我们的发现是艾滋病毒增加了一倍 使用其寡聚富含HIV包膜(Env)的葡聚糖膜作为附着因子可能提供一般原理 至少部分地解释：(I)阴道乳酸菌如何提供预防艾滋病毒传播的保护；以及(Ii)如何 阴道淋病奈瑟菌增加了艾滋病毒传播的风险。因为许多阴道微生物都有甘露糖- 与细菌表面的蛋白质和GlcNAc结合，我们的假设是寡聚体N- HIV Env上的多糖作为分子魔术贴与甘露糖结合蛋白和/或GlcNAc糖相互作用 在生殖器微生物的表面。我们进一步假设这些生殖器微生物的生物学 要么帮助捕获艾滋病毒以阻止他们感染宿主，要么充当快递服务将艾滋病毒传播到 主持人。我们将结合使用超微结构成像技术、生物物理方法、分子病毒学 技术，飞行时间细胞术(CyTOF)成像，葡聚糖基质辅助激光解吸电离- 质谱学成像(MALDI-MSI)和基于组织培养的上皮细胞模型系统来检测 通过两个特定的目的通过基于寡聚体的结合传播艾滋病毒。在Aim1中，我们将定义阴道 乳杆菌通过基于寡聚体的诱捕来限制艾滋病毒的传播。在AIM2中，我们将评估艾滋病毒是否搭便车穿越 通过寡聚体介导的淋病奈瑟菌结合的亚上皮下屏障。成功完成这项工作 提案可能导致概念数据的证明，即简单的基于寡聚体的机制可以解释 乳酸菌如何保护和淋球菌如何促进艾滋病毒传播分别具有相反的能力。 我们还将使用来自ATCC的预先设定的阴道微生物参考种群来评估这些基于多糖的 在人口层面上的相互作用。我们将对来自于 建立了与临床相关的南非艾滋病毒队列。显示基于寡聚体的相互作用的数据是 HIV性传播的促成因素可能为发展一种实用的、口服的 使用优化版本的GlcNAc或甘露糖提供自我给药的HIV缓解策略，考虑到这些 父母的单糖广泛可用，无毒，非处方药，营养食品。

PROJECT SUMMARY This proposal is built upon a novel discovery from the PI Mak laboratory showing that a ‘non-electrostatic, specific, manipulatable, sugar-sugar’ is an attachment factor for HIV. This interaction occurs between HIV oligomannose (oligoman) and cellular N-acetylglucosamine (GlcNAc) prior to receptor engagement. The conservation of glycan biology across domains of life and the non-living (viruses) has led to our current proposal to investigate whether this oligoman-GlcNAc (or oligoman-based) interaction may underpin some of the dynamic- interplays amongst: (i) vaginal microbes; (ii) HIV; and (iii) their human host. Our findings that HIV double up to use its oligoman enriched HIV envelope (Env) glycan shield as an attachment factor may offer a general principle to account, at least in part, for: (i) how vaginal lactobacillus offers protection from HIV transmission; and (ii) how vaginal Neisseria gonorrhoeae increases the risk of HIV transmission. As many vaginal microbes have mannose- binding proteins and GlcNAc on their bacterial surface, our hypothesis is that the enrichment of oligoman N- glycans on HIV Env acts as a molecular Velcro to interact with mannose-binding proteins and/or GlcNAc sugars on the surface of genital microbes. We further hypothesize that the biology of these genital microbes would either helps trap HIV to deny their access to infect the host or acts as a courier service to deliver HIV into the host. We will use a combination of ultrastructural imaging techniques, biophysical approaches, molecular virology techniques, cytometry by time of flight (CyTOF) -imaging, glycan matrix-assisted laser desorption ionization - mass spectrometry imaging (MALDI-MSI), and tissue culture-based epithelial cell model system to examine the transmission of HIV via oligoman-based binding via two specific aims. In Aim1, we will define whether vaginal lactobacillus limits HIV transmission via oligoman-based trapping. In Aim2, we will assess if HIV hitch-hike across sub-epithelial barrier via oligoman-mediated bindings with N.gonorrhoeae. Successful completion of this proposal may result in proof of concept data that a simple oligoman-based mechanism could account for the opposing abilities of how lactobacillus protect and how N.gonorrhoeae enhance HIV transmission, respectively. We will also use pre-set vaginal microbes reference population from ATCC to evaluate these glycan-based interaction at the population level. We will perform follow-up analyses with vaginal microbiomes derived from established and clinically relevant South African HIV cohort. Data showing oligoman-based interaction is a contributing factor to sexual transmission of HIV may offer new hope for the development of a practical, orally delivery self-administrated HIV mitigation strategy using optimised versions of GlcNAc or mannose, given these parental monosaccharides are widely available, non-toxic, off-the counter, nutraceuticals.