1887

Abstract

Human immunodeficiency virus type 1 (HIV-1) transmission often results from infection by a single transmitted/founder (T/F) virus. Here, we investigated the sensitivity of T/F HIV-1 envelope glycoproteins (Envs) to microbicide candidate carbohydrate-binding agents (CBAs) griffithsin (GRFT), cyanovirin-N (CV-N) and agglutinin (GNA), showing that T/F Envs demonstrated different sensitivity to CBAs, with IC values ranging from 0.006 ± 0.0003 to >10 nM for GRFT, from 0.6 ± 0.2 to 28.9 ± 2.9 nM for CV-N and from 1.3 ± 0.2 to >500 nM for GNA. We further revealed that deglycosylation at position 295 or 448 decreased the sensitivity of T/F Env to GRFT, and at 339 to both CV-N and GNA. Mutation of all the three glcyans rendered a CBA-sensitive T/F Env largely resistant to GRFT, indicating that the sensitivity of T/F Env to GRFT is mainly determined by glycans at 295, 339 and 448. Our study identified specific T/F Env residues associated with CBA sensitivity.

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2015-12-01
2024-12-06
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References

  1. Alexandre K. B., Gray E. S., Lambson B. E., Moore P. L., Choge I. A., Mlisana K., Karim S. S., McMahon J., O'Keefe B., other authors. 2010; Mannose-rich glycosylation patterns on HIV-1 subtype C gp120 and sensitivity to the lectins, Griffithsin, Cyanovirin-N and Scytovirin. Virology 402:187–196 [View Article][PubMed]
    [Google Scholar]
  2. Alexandre K. B., Moore P. L., Nonyane M., Gray E. S., Ranchobe N., Chakauya E., McMahon J. B., O'Keefe B. R., Chikwamba R., Morris L. 2013; Mechanisms of HIV-1 subtype C resistance to GRFT, CV-N and SVN. Virology 446:66–76 [View Article][PubMed]
    [Google Scholar]
  3. Auwerx J., François K. O., Covens K., Van Laethem K., Balzarini J. 2008; Glycan deletions in the HIV-1 gp120 V1/V2 domain compromise viral infectivity, sensitize the mutant virus strains to carbohydrate-binding agents and represent a specific target for therapeutic intervention. Virology 382:10–19 [View Article][PubMed]
    [Google Scholar]
  4. Balzarini J., Schols D., Neyts J., Van Damme E., Peumans W., De Clercq E. 1991; Alpha-(1-3)- and alpha-(1-6)-d-mannose-specific plant lectins are markedly inhibitory to human immunodeficiency virus and cytomegalovirus infections in vitro . Antimicrob Agents Chemother 35:410–416 [View Article][PubMed]
    [Google Scholar]
  5. Balzarini J., Van Laethem K., Hatse S., Froeyen M., Van Damme E., Bolmstedt A., Peumans W., De Clercq E., Schols D. 2005; Marked depletion of glycosylation sites in HIV-1 gp120 under selection pressure by the mannose-specific plant lectins of Hippeastrum hybrid and Galanthus nivalis . Mol Pharmacol 67:1556–1565 [View Article][PubMed]
    [Google Scholar]
  6. Balzarini J., Van Laethem K., Peumans W. J., Van Damme E. J., Bolmstedt A., Gago F., Schols D. 2006; Mutational pathways, resistance profile, and side effects of cyanovirin relative to human immunodeficiency virus type 1 strains with N-glycan deletions in their gp120 envelopes. J Virol 80:8411–8421 [View Article][PubMed]
    [Google Scholar]
  7. Bewley C. A. 2001; Solution structure of a cyanovirin-N : Manα1-2Manα complex: structural basis for high-affinity carbohydrate-mediated binding to gp120. Structure 9:931–940 [View Article][PubMed]
    [Google Scholar]
  8. Boyd M. R., Gustafson K. R., McMahon J. B., Shoemaker R. H., O'Keefe B. R., Mori T., Gulakowski R. J., Wu L., Rivera M. I., other authors. 1997; Discovery of cyanovirin-N, a novel human immunodeficiency virus-inactivating protein that binds viral surface envelope glycoprotein gp120: potential applications to microbicide development. Antimicrob Agents Chemother 41:1521–1530[PubMed]
    [Google Scholar]
  9. François K. O., Balzarini J. 2012; Potential of carbohydrate-binding agents as therapeutics against enveloped viruses. Med Res Rev 32:349–387 [View Article][PubMed]
    [Google Scholar]
  10. Go E. P., Hewawasam G., Liao H. X., Chen H., Ping L. H., Anderson J. A., Hua D. C., Haynes B. F., Desaire H. 2011; Characterization of glycosylation profiles of HIV-1 transmitted/founder envelopes by mass spectrometry. J Virol 85:8270–8284 [View Article][PubMed]
    [Google Scholar]
  11. Haaland R. E., Hawkins P. A., Salazar-Gonzalez J., Johnson A., Tichacek A., Karita E., Manigart O., Mulenga J., Keele B. F., other authors. 2009; Inflammatory genital infections mitigate a severe genetic bottleneck in heterosexual transmission of subtype A and C HIV-1. PLoS Pathog 5:e1000274 [View Article][PubMed]
    [Google Scholar]
  12. Hu Q., Mahmood N., Shattock R. J. 2007; High-mannose-specific deglycosylation of HIV-1 gp120 induced by resistance to cyanovirin-N and the impact on antibody neutralization. Virology 368:145–154 [View Article][PubMed]
    [Google Scholar]
  13. Huang X., Jin W., Griffin G. E., Shattock R. J., Hu Q. 2011; Removal of two high-mannose N-linked glycans on gp120 renders human immunodeficiency virus 1 largely resistant to the carbohydrate-binding agent griffithsin. J Gen Virol 92:2367–2373 [View Article][PubMed]
    [Google Scholar]
  14. Huskens D., Vermeire K., Vandemeulebroucke E., Balzarini J., Schols D. 2008; Safety concerns for the potential use of cyanovirin-N as a microbicidal anti-HIV agent. Int J Biochem Cell Biol 40:2802–2814 [View Article][PubMed]
    [Google Scholar]
  15. Keele B. F., Giorgi E. E., Salazar-Gonzalez J. F., Decker J. M., Pham K. T., Salazar M. G., Sun C., Grayson T., Wang S., other authors. 2008; Identification and characterization of transmitted and early founder virus envelopes in primary HIV-1 infection. Proc Natl Acad Sci U S A 105:7552–7557 [View Article][PubMed]
    [Google Scholar]
  16. Leonard C. K., Spellman M. W., Riddle L., Harris R. J., Thomas J. N., Gregory T. J. 1990; Assignment of intrachain disulfide bonds and characterization of potential glycosylation sites of the type 1 recombinant human immunodeficiency virus envelope glycoprotein (gp120) expressed in Chinese hamster ovary cells. J Biol Chem 265:10373–10382[PubMed]
    [Google Scholar]
  17. Mori T., O'Keefe B. R., Sowder R. C. II, Bringans S., Gardella R., Berg S., Cochran P., Turpin J. A., Buckheit R. W. Jr, other authors. 2005; Isolation and characterization of griffithsin, a novel HIV-inactivating protein, from the red alga Griffithsia sp. J Biol Chem 280:9345–9353 [View Article][PubMed]
    [Google Scholar]
  18. Shaw T. I., Zhang M. 2013; HIV N-linked glycosylation site analyzer and its further usage in anchored alignment. Nucleic Acids Res 41:(W1)W454–W458 [View Article][PubMed]
    [Google Scholar]
  19. Tsai C. C., Emau P., Jiang Y., Tian B., Morton W. R., Gustafson K. R., Boyd M. R. 2003; Cyanovirin-N gel as a topical microbicide prevents rectal transmission of SHIV89.6P in macaques. AIDS Res Hum Retroviruses 19:535–541 [View Article][PubMed]
    [Google Scholar]
  20. Tsai C. C., Emau P., Jiang Y., Agy M. B., Shattock R. J., Schmidt A., Morton W. R., Gustafson K. R., Boyd M. R. 2004; Cyanovirin-N inhibits AIDS virus infections in vaginal transmission models. AIDS Res Hum Retroviruses 20:11–18 [View Article][PubMed]
    [Google Scholar]
  21. Van Damme E. J. M., Allen A. K., Peumans W. J. 1987; Isolation and characterization of a lectin with exclusive specificity towards mannose from snowdrop (Galanthus nivalis) bulbs. FEBS Lett 215:140–144 [View Article]
    [Google Scholar]
  22. Ziółkowska N. E., O'Keefe B. R., Mori T., Zhu C., Giomarelli B., Vojdani F., Palmer K. E., McMahon J. B., Wlodawer A. 2006; Domain-swapped structure of the potent antiviral protein griffithsin and its mode of carbohydrate binding. Structure 14:1127–1135 [View Article][PubMed]
    [Google Scholar]
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