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High-mannose-specific deglycosylation of HIV-1 gp120 induced by resistance to cyanovirin-N and the impact on antibody neutralization.

Hu Q, Mahmood N, Shattock RJ

Center for Infection, Department of Cellular and Molecular Medicine, St George's University of London, London SW17 0RE, UK.

HIV-1 uses glycans on gp120 to occlude its highly immunogenic epitopes. To better elucidate escape mechanisms of HIV-1 from carbohydrate-binding agents (CBA) and to understand the impact of CBA-escape on viral immune evasion, we generated and examined the biological properties of HIV-1 resistant to cyanovirin-N (CV-N) or cross-resistant to additional CBAs. Genotypic and phenotypic characterization of resistant env clones indicated that 3-5 high-mannose residues from 289 to 448 in the C2-C4 region of gp120 were mutated and correlated with the resistance levels. The specificity and minimal requirements of deglycosylation for CV-N resistance were further assessed by mutagenesis study. The sensitivity of resistant variants to a range of CBAs, immunoglobulins, sera and monoclonal antibodies (MAb) were investigated. For the first time, our data have collectively defined the high-mannose residues on gp120 affecting CV-N activity, and demonstrated that CBA-escape HIV-1 has increased sensitivity to immunoglobulins and sera from HIV patients, and particularly to V3 loop-directed MAbs. Our study provides a proof-of-concept that targeting HIV-1 glycan shields may represent a novel antiviral strategy.

Published 26 October 2007 in Virology, 368(1): 145-54.
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