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Via lectin-mediated interactions, the gp120 glycans may trap viruses at the mucosal interface, enhance trans-infection of CD4+ T cells, or enhance HIV uptake for antigen presentation while limiting such presentation by inhibiting gp120 proteolysis. Also, variations in numbers and location of glycosylation sites may allow escape from emerging neutralizing antibodies. Thus, specific gp120 glycans may be critical for transmission and immune control. As most transmission events arise from a single transmitted founder virus (T\/F), we surmise that a unique glycosylation signature in T\/F viruses supports optimal transmission and could be targeted for vaccination. By combining mass spectrometry, computational analyses, structural modeling and lectin microarrays, this study provides a comprehensive, quantitative and site-specific analysis of gp120 N-glycosylation and its functional impact. The 24 and 27\u00a0N-linked glycosylation sites of gp120 from a T\/F and a chronic HIV-1 isolate were interrogated for 55 glycoforms representing glycosylation steps across the endoplasmic reticulum and the Golgi. We showed that gp120 is more glycosylated in T\/F virions than in chronic virions, both having unique glycosylation hot spots that influence lectin binding. These site-specific glycosylation differences may correlate with differential transmission fitness of the isolates. This proof-of-principle study will enable large-scale comparisons of complex N-glycosylation patterns of T\/F and chronic viruses to fully test if unique glycan signatures influence HIV transmissibility and can be exploited for vaccine development.<\/jats:p>","DOI":"10.1093\/glycob\/cwag021","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T12:44:40Z","timestamp":1774529080000},"source":"Crossref","is-referenced-by-count":0,"title":["Comprehensive analysis of gp120 glycosylation to explore differences between transmitter\/founder and chronic HIV-1 isolates"],"prefix":"10.1093","volume":"36","author":[{"given":"Stephen","family":"Temesy","sequence":"first","affiliation":[{"name":"Department of Microbiology & Immunology, Dental Sciences Building, Western University , London, ON, N6A 5C1 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