High-mannose-specific deglycosylation of HIV-1 gp120 induced by resistance to cyanovirin-N and the impact on antibody neutralization.
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.
Center for Infection, Department of Cellular and Molecular Medicine, St George's University of London, London SW17 0RE, UK.
Qinxue
Q
Hu
Naheed
N
Mahmood
Robin J
RJ
Shattock
D019943:Amino Acid Substitution / Q000235:genetics; D019380:Anti-HIV Agents / Q000494:pharmacology; D000914:Antibodies, Viral / Q000276:immunology; D001426:Bacterial Proteins / Q000494:pharmacology*; D002352:Carrier Proteins / Q000494:pharmacology*; D004252:DNA Mutational Analysis; D024882:Drug Resistance, Viral; D006031:Glycosylation; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000276:immunology*; D006801:Humans; D008358:Mannose / Q000276:immunology* / Q000378:metabolism*; D009500:Neutralization Tests
D019380:Anti-HIV Agents; D000914:Antibodies, Viral; D001426:Bacterial Proteins; D002352:Carrier Proteins; D015699:HIV Envelope Protein gp120; C514793:gp120 protein, Human immunodeficiency virus 1; C107733:cyanovirin N; D008358:Mannose