Dichotomy of HIV-Sugar with Vaginal Microbes

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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.