Dichotomy of HIV-Sugar with Vaginal Microbes

HIV-糖与阴道微生物的二分法

• 批准号: 10693740
• 负责人: Johnson Mak
• 金额: $ 14.85万
• 依托单位: GRIFFITH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-24 至 2025-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10693740
• 关键词: Bacteria; Bacterial Infections; Bacterial Vaginosis; Binding; Biological Models; Biology; CCR5 gene; CD4 Antigens; Cell surface; Cells; Cervical; Clinical; Cytometry; Data; Dendritic Cells; Development; Electron Microscopy; Electrostatics; Epithelial Cells; Epithelium; Eukaryotic Cell; Exhibits; Genetic; Genital; Genitalia; Glycoconjugates; Glycoside Hydrolases; HIV; HIV Infections; HIV Receptors; HIV envelope protein; Human; Image; Imaging Techniques; Immune; In Vitro; Infection; Inflammation; Inflammatory; Invaded; Laboratories; Lactobacillus; Langerhans cell; Language; Lectin; Life; Liquid substance; Male Circumcision; Mannose; Mannose Binding Lectin; Mediating; Microbe; Microbial Biofilms; Modeling; Molecular; Molecular Cloning; Molecular Virology; Monosaccharides; Movement; Neisseria gonorrhoeae; Nutraceutical; Oral; Outcome; Phenotype; Polysaccharides; Population; Process; Production; Recombinants; Reporter; Resource-limited setting; Risk; Risk Reduction; Role; Route; Services; Sexual Transmission; Sexually Transmitted Diseases; South African; Specificity; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Surface; Surface Plasmon Resonance; T-Lymphocyte; Techniques; Tight Junctions; Time; Trauma; Urethra; Vagina; Vaginal Douching; Viral; Virus; biophysical analysis; biophysical techniques; cell killing; cervicovaginal; clinically relevant; cohort; follow-up; glycosylation; in vivo; mass spectrometric imaging; nanoluciferase; neutrophil; novel; particle; pathogenic virus; penile microbiome; preference; receptor; sexual HIV transmission; sialoadhesin; sugar; tissue culture; transmission process; vaginal lactobacilli; vaginal microbiome

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.

项目总结