1887

Abstract

In the absence of a protective vaccine against human immunodeficiency virus (HIV), there is an urgent need for the development of effective topical microbicides to prevent HIV infection. Candidate vaginal microbicides should provide protection against circulating strains, be cheap, stable on storage, safe and easy to use. Here we describe a detailed study of the safety and efficacy of Cyanovirin-N (CV-N) , and in an model of female genital tissue explants. CV-N demonstrated potent activity in the low nanomolar range against laboratory and primary isolates. Activity was related to the affinity of CV-N for binding to whole virions as determined by acoustic resonance. Potent activity was also observed against cell-associated HIV-1, although slightly reduced. CV-N activity in the presence of whole semen was reduced by 7–10-fold, although it remained in the low nanomolar range and was minimally modified by the presence of . Furthermore, CV-N potently inhibited infection of ectocervical explants and virus dissemination by tissue-emigrating cells. In peripheral blood mononuclear cell (PBMC) assays, CV-N was shown to have some mitogenic activity following 3 days exposure to compound, and this was associated with a modest increase in expression of gamma interferon, stromal cell-derived factor 1 and interleukin 4. However, 2 h exposure to CV-N had no effect on cytokine expression in PBMC or tissue explant culture over a 24 h period, suggesting that the potential for inflammation is low. Data presented here indicate that targeting HIV envelope glycoproteins may provide an effective strategy to prevent HIV-1 infection mediated by either cell-free virus or infected cells.

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2009-01-01
2019-11-21
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References

  1. Balzarini, J. & Van Damme, L. ( 2007; ). Microbicide drug candidates to prevent HIV infection. Lancet 369, 787–797.[CrossRef]
    [Google Scholar]
  2. 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.[CrossRef]
    [Google Scholar]
  3. Balzarini, J., Van Herrewege, Y., Vermeire, K., Vanham, G. & Schols, D. ( 2007; ). Carbohydrate-binding agents efficiently prevent dendritic cell-specific intercellular adhesion molecule-3-grabbing nonintegrin (DC-SIGN)-directed HIV-1 transmission to T lymphocytes. Mol Pharmacol 71, 3–11.
    [Google Scholar]
  4. Barrientos, L. G. & Gronenborn, A. M. ( 2005; ). The highly specific carbohydrate-binding protein cyanovirin-N: structure, anti-HIV/Ebola activity and possibilities for therapy. Mini Rev Med Chem 5, 21–31.[CrossRef]
    [Google Scholar]
  5. Bouhlal, H., Chomont, N., Haeffner-Cavaillon, N., Kazatchkine, M. D., Belec, L. & Hocini, H. ( 2002; ). Opsonization of HIV-1 by semen complement enhances infection of human epithelial cells. J Immunol 169, 3301–3306.[CrossRef]
    [Google Scholar]
  6. 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.
    [Google Scholar]
  7. Dhawan, D., Keller, M. & Klotman, M. E. ( 2006; ). Topical microbicides: the time has come. AIDS Read 16, 144–148.
    [Google Scholar]
  8. Dupont, B., Graybill, J. R., Armstrong, D., Laroche, R., Touzé, J. E. & Wheat, L. J. ( 1992; ). Fungal infections in AIDS patients. J Med Vet Mycol 30 (Suppl. 1), 19–28.[CrossRef]
    [Google Scholar]
  9. Esser, M. T., Mori, T., Mondor, I., Sattentau, Q. J., Dey, B., Berger, E. A., Boyd, M. R. & Lifson, J. D. ( 1999; ). Cyanovirin-N binds to gp120 to interfere with CD4-dependent human immunodeficiency virus type 1 virion binding, fusion, and infectivity but does not affect the CD4 binding site on gp120 or soluble CD4-induced conformational changes in gp120. J Virol 73, 4360–4371.
    [Google Scholar]
  10. Esser, M. T., Graham, D. R., Coren, L. V., Trubey, C. M., Bess, J. W., Jr, Arthur, L. O., Ott, D. E. & Lifson, J. D. ( 2001; ). Differential incorporation of CD45, CD80 (B7–1), CD86 (B7–2), and major histocompatibility complex class I and II molecules into human immunodeficiency virus type 1 virions and microvesicles: implications for viral pathogenesis and immune regulation. J Virol 75, 6173–6182.[CrossRef]
    [Google Scholar]
  11. European Study Group on Heterosexual Transmission of HIV ( 1992; ). Comparison of female to male and male to female transmission of HIV in 563 stable couples. BMJ 304, 809–813.[CrossRef]
    [Google Scholar]
  12. Fichtenbaum, C. J. & Powderly, W. G. ( 1998; ). Refractory mucosal candidiasis in patients with human immunodeficiency virus infection. Clin Infect Dis 26, 556–565.[CrossRef]
    [Google Scholar]
  13. Fletcher, P., Kiselyeva, Y., Wallace, G., Romano, J., Griffin, G., Margolis, L. & Shattock, R. ( 2005; ). The nonnucleoside reverse transcriptase inhibitor UC-781 inhibits human immunodeficiency virus type 1 infection of human cervical tissue and dissemination by migratory cells. J Virol 79, 11179–11186.[CrossRef]
    [Google Scholar]
  14. Fletcher, P. S., Wallace, G. S., Mesquita, P. M. & Shattock, R. J. ( 2006; ). Candidate polyanion microbicides inhibit HIV-1 infection and dissemination pathways in human cervical explants. Retrovirology 3, 46 [CrossRef]
    [Google Scholar]
  15. Greenhead, P., Hayes, P., Watts, P. S., Laing, K. G., Griffin, G. E. & Shattock, R. J. ( 2000; ). Parameters of human immunodeficiency virus infection of human cervical tissue and inhibition by vaginal virucides. J Virol 74, 5577–5586.[CrossRef]
    [Google Scholar]
  16. Helle, F., Wychowski, C., Vu-Dac, N., Gustafson, K. R., Voisset, C. & Dubuisson, J. ( 2006; ). Cyanovirin-N inhibits hepatitis C virus entry by binding to envelope protein glycans. J Biol Chem 281, 25177–25183.[CrossRef]
    [Google Scholar]
  17. Honey, K. ( 2007; ). Microbicide trial screeches to a halt. J Clin Invest 117, 1116 [CrossRef]
    [Google Scholar]
  18. Hu, Q., Frank, I., Williams, V., Santos, J. J., Watts, P., Griffin, G. E., Moore, J. P., Pope, M. & Shattock, R. J. ( 2004; ). Blockade of attachment and fusion receptors inhibits HIV-1 infection of human cervical tissue. J Exp Med 199, 1065–1075.[CrossRef]
    [Google Scholar]
  19. 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.[CrossRef]
    [Google Scholar]
  20. Ketas, T. J., Schader, S. M., Zurita, J., Teo, E., Polonis, V., Lu, M., Klasse, P. J. & Moore, J. P. ( 2007; ). Entry inhibitor-based microbicides are active in vitro against HIV-1 isolates from multiple genetic subtypes. Virology 364, 431–440.[CrossRef]
    [Google Scholar]
  21. Klasse, P. J., Shattock, R. & Moore, J. P. ( 2008; ). Antiretroviral drug-based microbicides to prevent HIV-1 sexual transmission. Annu Rev Med 59, 455–471.[CrossRef]
    [Google Scholar]
  22. Li, M., Gao, F., Mascola, J. R., Stamatatos, L., Polonis, V. R., Koutsoukos, M., Voss, G., Goepfert, P., Gilbert, P. & other authors ( 2005; ). Human immunodeficiency virus type 1 env clones from acute and early subtype B infections for standardized assessments of vaccine-elicited neutralizing antibodies. J Virol 79, 10108–10125.[CrossRef]
    [Google Scholar]
  23. Li, X., Thompson, K. S., Godber, B. & Cooper, M. A. ( 2006; ). Quantification of small molecule-receptor affinities and kinetics by acoustic profiling. Assay Drug Dev Technol 4, 565–573.[CrossRef]
    [Google Scholar]
  24. Lillegard, J. B., Sim, R. B., Thorkildson, P., Gates, M. A. & Kozel, T. R. ( 2006; ). Recognition of Candida albicans by mannan-binding lectin in vitro and in vivo. J Infect Dis 193, 1589–1597.[CrossRef]
    [Google Scholar]
  25. Mosmann, T. ( 1983; ). Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65, 55–63.[CrossRef]
    [Google Scholar]
  26. Neurath, A. R., Strick, N. & Li, Y. Y. ( 2006; ). Role of seminal plasma in the anti-HIV-1 activity of candidate microbicides. BMC Infect Dis 6, 150–160.[CrossRef]
    [Google Scholar]
  27. Patel, S., Hazrati, E., Cheshenko, N., Galen, B., Yang, H., Guzman, E., Wang, R., Herold, B. C. & Keller, M. J. ( 2007; ). Seminal plasma reduces the effectiveness of topical polyanionic microbicides. J Infect Dis 196, 1394–1402.[CrossRef]
    [Google Scholar]
  28. Quinn, T. C. & Overbaugh, J. ( 2005; ). HIV/AIDS in women: an expanding epidemic. Science 308, 1582–1583.[CrossRef]
    [Google Scholar]
  29. Sabatté, J., Ceballos, A., Raiden, S., Vermeulen, M., Nahmod, K., Maggini, J., Salamone, G., Salomón, H., Amigorena, S. & Geffner, J. ( 2007; ). Human seminal plasma abrogates the capture and transmission of human immunodeficiency virus type 1 to CD4+ T cells mediated by DC-SIGN. J Virol 81, 13723–13734.[CrossRef]
    [Google Scholar]
  30. Segura, M. M., Garnier, A. & Kamen, A. ( 2006; ). Purification and characterization of retrovirus vector particles by rate zonal ultracentrifugation. J Virol Methods 133, 82–91.[CrossRef]
    [Google Scholar]
  31. Shattock, R. J. & Moore, J. P. ( 2003; ). Inhibiting sexual transmission of HIV-1 infection. Nat Rev Microbiol 1, 25–34.[CrossRef]
    [Google Scholar]
  32. Shattock, R. & Solomon, S. ( 2004; ). Microbicides – aids to safer sex. Lancet 363, 1002–1003.[CrossRef]
    [Google Scholar]
  33. Shenoy, S. R., O'Keefe, B. R., Bolmstedt, A. J., Cartner, L. K. & Boyd, M. R. ( 2001; ). Selective interactions of the human immunodeficiency virus-inactivating protein cyanovirin-N with high-mannose oligosaccharides on gp120 and other glycoproteins. J Pharmacol Exp Ther 297, 704–710.
    [Google Scholar]
  34. Trubey, C. M., Chertova, E., Coren, L. V., Hilburn, J. M., Hixson, C. V., Nagashima, K., Lifson, J. D. & Ott, D. E. ( 2003; ). Quantitation of HLA class II protein incorporated into human immunodeficiency type 1 virions purified by anti-CD45 immunoaffinity depletion of microvesicles. J Virol 77, 12699–12709.[CrossRef]
    [Google Scholar]
  35. 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.[CrossRef]
    [Google Scholar]
  36. 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.[CrossRef]
    [Google Scholar]
  37. Turville, S. G., Vermeire, K., Balzarini, J. & Schols, D. ( 2005; ). Sugar-binding proteins potently inhibit dendritic cell human immunodeficiency virus type 1 (HIV-1) infection and dendritic-cell-directed HIV-1 transfer. J Virol 79, 13519–13527.[CrossRef]
    [Google Scholar]
  38. UNAIDS/WHO ( 2007; ). AIDS epidemic update. WHO Library Cataloguing-in-Publication Data. UNAIDS/07.27E/JC1322E. http://data.unaids.org/pub/EPISlides/2007/2007_epiupdate_en.pdf
  39. Van Damme, L., Ramjee, G., Alary, M., Vuylsteke, B., Chandeying, V., Rees, H., Sirivongrangson, P., Mukenge-Tshibaka, L. & other authors ( 2002; ). Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial. Lancet 360, 971–977.[CrossRef]
    [Google Scholar]
  40. Wei, X., Decker, J. M., Liu, H., Zhang, Z., Arani, R. B., Kilby, J. M., Saag, M. S., Wu, X., Shaw, G. M. & Kappes, J. C. ( 2002; ). Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother 46, 1896–1905.[CrossRef]
    [Google Scholar]
  41. Witvrouw, M., Fikkert, V., Hantson, A., Pannecouque, C., O'Keefe, B. R., McMahon, J., Stamatatos, L., de Clercq, E. & Bolmstedt, A. ( 2005; ). Resistance of human immunodeficiency virus type 1 to the high-mannose binding agents cyanovirin N and concanavalin A. J Virol 79, 7777–7784.[CrossRef]
    [Google Scholar]
  42. Zhu, T., Mo, H., Wang, N., Nam, D. S., Cao, Y., Koup, R. A. & Ho, D. D. ( 1993; ). Genotypic and phenotypic characterization of HIV-1 patients with primary infection. Science 261, 1179–1181.[CrossRef]
    [Google Scholar]
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