Microbicides for topical immunoprevention of HIV infection
https://doi.org/10.20538/1682-0363-2019-1-49-59
Abstract
Microbicides are antiseptic topical drugs that help directly or indirectly inhibit the penetration of an infectious agent into the human body, thereby preventing the sexual transmission of HIV-infection and other sexually transmitted diseases. Microbicides have an antiviral mechanism of action in the sexual transmission of HIV and affect the components of mucosal immunity in the vagina. In this article, the pharmaceutical and biomedical aspects of microbicide application are examined and diverse classifications of microbicides are presented. For each group of chemicals, the most important representatives and their mechanisms of action are described. This article also presents the structure and function of mucosal immunity, and shows the importance of the mucosal immune response in the sexual transmission of HIV. This work also exhibits the experimental models for testing of candidate microbicides. For each compound described, a review of preclinical research and clinical trials is provided, covering its development as a microbicide. This paper gives an overview of microbicides, a new class of chemically diverse immunobiological medications reducing the risk of sexual transmission of HIV. The use of microbicides is believed to curb the HIV/AIDS epidemic in the nearest future.
About the Authors
Yu. V. Zhernov
Institute of Immunology
Russian Federation
Russian Federation
Zhernov Yury V., PhD, Head of the Laboratory of Innate Immunity
24, Kashirskoe Sh., Moscow, 115478
M. R. Khaitov
Institute of Immunology
Russian Federation
Russian Federation
Khaitov Musa R., DМ, Professor, Corresponding Member of RAS, Director of Institute of Immunology
24, Kashirskoe Sh., Moscow, 115478
References
1. Khaitov R.M. AIDS. 2nd edition, revised and supplemented. Moscow: GEOTAR-Media Publ., 2018: 496 (in Russ.).
2. Karamov E.V., Gashnikova N.M., Drozdov I.G., Onishchenko G.G. Monitoring of HIV infection in Eurasia. Atlas of human immunodeficiency viruses. Novosibirsk: TSERIS Publ., 2009: 418 (in Russ.).
3. Weber J., Tatoud R., Fidler S. Postexposure prophylaxis, preexposure prophylaxis or universal test and treat: the strategic use of antiretroviral drugs to prevent HIV acquisition and transmission. AIDS. 2010; Suppl. 4: 27–39. DOI: 10.1097/01.aids.0000390705.73759.2c.
4. Stover J., Bertozzi S., Gutierrez J.P., Walker N., Stanecki K.A., Greener R., Gouws E., Hankins C., Garnett G.P., Salomon J.A., Boerma J.T., De Lay P., Ghys P.D. The global impact of scaling up HIV/AIDS prevention programs in low- and middle-income countries. Science. 2006; 311 (5766): 1474–1476. DOI: 10.1126/science.1121176.
5. Quinn T.C., Overbaugh J. HIV/AIDS in women: an expanding epidemic. Science. 2005; 308: 1582–1583. DOI: 10.1126/science.1112489.
6. Delva W., Abdool Karim Q. The HIV Epidemic in Southern Africa – Is an AIDS-Free Generation Possible? Curr. HIV/AIDS Rep. 2014; 11 (2): 99–108. DOI: 10.1007/s11904-014-0205-0.
7. Gudima G.O., Sidorovich I.G., Karamov E.V., Khaitov R.M. Modern strategies for biomedical HIV/AIDS prevention. Part 1. Anti-HIV/ AIDS vaccines and antiretroviral therapy. Immunology. 2013; 34 (1): 4–9 (in Russ.).
8. Grant R.M., Lama J.R., Anderson P.L., McMahan V., Liu A.Y., Vargas L., Goicochea P., Casapнa M., Guanira-Carranza J.V., Ramirez-Cardich M.E., Montoya-Herrera O., Fernández T., Veloso V.G., Buchbinder S.P., Chariyalertsak S., Schechter M., Bekker L.G., Mayer K.H., Kallás E.G., Amico K.R., Mulligan K., Bushman L.R., Hance R.J., Ganoza C., Defechereux P., Postle B., Wang F., McConnell J.J., Zheng J.H., Lee J., Rooney J.F., Jaffe H.S., Martinez A.I., Burns D.N., Glidden D.V. iPrEx Study Team. Preexposure chemoprophylaxis for HIV prevention in men who have sex with men. N. Engl. J. Med. 2010; 363 (27): 2587–2599. DOI: 10.1056/NEJMoa1011205.
9. Shattock R.J., Moore J.P. Inhibiting sexual transmission of HIV-1 infection. Nat. Rev. Microbiol. 2003; 1 (1): 25– 34. DOI: 10.1038/nrmicro729.
10. Mesman A.W., Geijtenbeek T.B. Pattern recognition receptors in HIV transmission. Front. Immunol. 2012; 3: 59. DOI: 10.3389/fimmu.2012.00059.
11. Cunningham A.L., Harman A., Nasr N. Initial HIV mucosal infection and dendritic cells. EMBO Mol. Med. 2013; 5 (5): 658–660. DOI: 10.1002/emmm.201202763.
12. Ochsenbauer C., Edmonds T.G., Ding H., Keele B.F., Decker J., Salazar M.G., Salazar-Gonzalez J.F., Shattock R., aynes B.F., Shaw G.M., Hahn B.H., Kappes J.C. Generation of transmitted/founder HIV-1 infectious molecular clones and characterization of their replication capacity in CD4 T lymphocytes and monocyte-derived macrophages. J. Virol. 2012; 86 (5): 2715–2728. DOI: 10.1128/JVI.06157-11.
13. Harman A.N., Kim M., Nasr N., Sandgren K.J., Cameron P.U. Tissue dendritic cells as portals for HIV entry. Rev. Med. Virol. 2013; 23 (5): 319–333. DOI: 10.1002/rmv.1753.
14. Parrish N.F., Gao F., Li H., Giorgi E.E., Barbian H.J., Parrish E.H., Zajic L., Iyer S.S., Decker J.M., Kumar A., Hora B., Berg A., Cai F., Hopper J., Denny T.N., Ding H., Ochsenbauer C., Kappes J.C., Galimidi R.P., West A.P. Jr., Bjorkman P.J., Wilen C.B., Doms R.W., O’Brien M., Bhardwaj N., Borrow P., Haynes B.F., Muldoon M., Theiler J.P., Korber B., Shaw G.M., Hahn B.H. Phenotypic properties of transmitted founder HIV-1. Proc. Natl. Acad. Sci. USA. 2013; 110 (17): 6626–6633. DOI: 10.1073/pnas.1304288110.
15. Letvin N.L. Progress and obstacles in the development of an AIDS vaccine. Nat. Rev. Immunol. 2006; 6 (12): 930–939. DOI: 10.1038/nri1959.
16. Chang S.Y., Ko H.J., Kweon M.N. Mucosal dendritic cells shape mucosal immunity. Exp. Mol. Med. 2014; 46: e84. DOI: 10.1038/emm.2014.16.
17. Brandtzaeg P., Johansen F.E. Mucosal B cells: phenotypic characteristics, transcriptional regulation, and homing properties. Immunol. Rev. 2005; 206: 32–63. DOI: 10.1111/j.0105-2896.2005.00283.x.
18. Cerutti A., Chen K., Chorny A. Immunoglobulin responses at the mucosal interface. Annu. Rev. Immunol. 2011; 29: 273–293. DOI: 10.1146/annurev-immunol-031210-101317.
19. Su B., Xu K., Leder le A., Peressin M., Biedma M.E., Laumond G., Schmidt S., Decoville T., Proust A., Lambotin M., Holl V., Moog C. Neutralizing antibodies inhibit HIV-1 transfer from primary dendritic cells to autologous CD4 T lymphocytes. Blood. 2012; 120 (18): 3708– 3717. DOI: 10.1182/blood-2012-03-418913.
20. Patton D.L., Sweeney Y.T., Balkus J.E., Hillier S.L. Vaginal and rectal topical microbicide develop-ment: safety and efficacy of 1.0% Savvy (C31G) in the pigtailed macaque. Sex Transm. Dis. 2006; 33 (11): 691–695. DOI: 10.1097/01.olq.0000216022.18321.d3.
21. Van Damme L., Ramjee G., Alary M., Vuylsteke B., Chandeying V., Rees H., Sirivongrangson P., Mukenge-Tshibaka L., Ettiègne-Traoré V., Uaheowitchai C., Karim S.S., Mâsse B., Perriëns J., Laga M; COL-1492 Study Group. Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial. Lancet. 2002; 360 (9338): 971–977. DOI: 10.1016/S0140-6736(02)11079-8.
22. Peterson L., Nanda K., Opoku B.K., Ampofo W.K., Owusu-Amoako M., Boakye A.Y., Rountree W., Troxler A., Dominik R., Roddy R., Dorflinger L.. SAVVY (C31G) gel for prevention of HIV infection in women: a Phase 3, double-blind, randomized, placebo-controlled trial in Ghana. PLoS One. 2007; 2 (12): e1312. DOI: 10.1371/journal.pone.0001312.
23. Piret J., Desormeaux A., Bergeron M.G. Sodium lauryl sulfate, a microbicides effective against envel-oped and nonenveloped viruses. Curr. Drug Targets. 2002; 3 (1): 17–30. DOI: 10.2174/1389450023348037.
24. Zeitlin L., Hoen T.E., Achilles S.L., Hegarty T.A., Jerse A.E., Kreider J.W., Olmsted S.S., Whaley K.J., Cone R.A., Moench T.R. Tests of Buffergel for contraception and prevention of sexually transmitted diseases in animal models. Sex Transm. Dis. 2001. 28 (7): 417–423. DOI: 10.1097/00007435-200107000-00010.
25. Van De Wijgert J., Fullem A., Kelly C., Mehendale S., Rugpao S., Kumwenda N., Chirenje Z., Joshi S., Taha T., Padian N., Bollinger R., Nelson K. Phase 1 Trial of the Topical Microbicide BufferGel: Safety Results From Four International Sites. J. Acquir. Immune Defic. Syndr. 2001; 26 (1): 21–27. DOI: 10.1097/00126334-200101010-00003.
26. Neurath A.R., Strick N., Li Y.Y. Anti-HTV-1 activity of anionic polymers: a comparative study of can-didate microbicides. BMC Infect. Dis. 2002; 2: 27. DOI: 10.1186/1471-2334-2-27.
27. Skoler-Karpoff S., Ramjee G., Ahmed K., Altini L., Plagianos M.G., Friedland B., Govender S., De Kock A., Cassim N., Palanee T., Dozier G., Maguire R., Lahteenmaki P. Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial. Lancet. 2008; 372 (9654): 1977–1987. DOI: 10.1016/S0140-6736(08)61842-5.
28. Fletcher P.S., Wallace G.S., Mesquita P.M., Shattock R.J. Candidate polyanion microbicides inhibit HIV-1 infection and dissemination pathways in human cervical explants. Retrovirology. 2006; 3: 46. DOI: 10.1186/1742-4690-3-46.
29. Zhernov Y.V., Krem S., Helfer M., Schindler M., Harir M., Mueller C., Hertkorn N., Avvakumova N.P., Konstantinov A.I., Brack-Werner R., Schmitt-Kopplindg P., Perminova I.V. Supramolecular combinations of humic polyanions as potent microbicides with polymodal anti-HIV-activities. New J. Chem. 2017; 41: 212–224. DOI: 10.1039/C6NJ00960C.
30. Zhernov Y. Natural humic substances interfere with multiple stages of the replication cycle of human immunodeficiency virus. J. Allergy. Clin. Immunol. 2018; 141 (2): AB233. DOI: 10.1016/j.jaci.2017.12.737.
31. Zhernov Yu.V. Analysis of cytotoxicity of humic substances of peloids. Izvestiya Samarskogo nauchnogo centr RAN. 2011; 13 (39): 1996–1998 (in Russ.).
32. Avvakumova N.P., Zhdanova A.V., Glubokova M.N., Zhernov Yu.V. The effect of humic acids on the processes of free radical oxidation. Izvestiya Samarskogo nauchnogo centra RAN. 2011; 13 (8): 1960–1963 (in Russ.).
33. Schneider J., Weis R., Manner C., Kary B., Werner A., Seubert B.J., Riede U.N. Inhibition of HIV-1 in cell culture by synthetic humate analogues derived from hydroquinone: mechanism of inhibition. Virology. 1996; 218 (2): 389–395. DOI: 10.1006/viro.1996.0208.
34. Joone G.K., Dekker J., van Rensburg C.E. Investigation of the immunostimulatory properties of oxihu-mate. Z. Naturforsch C. 2003; 58 (3–4): 263–267. DOI: 10.1515/znc-2003-3-421.
35. O’Keefe B.R., Vojdani F., Buffa V., Shattock R.J., Montefiori D.C., Bakke J., Mirsalis J., d’Andrea A.L., Hume S.D., Bratcher B., Saucedo C.J., McMahon J.B., Pogue G.P., Palmer K.E. Scaleable manufacture of HIV- 1 entry inhibitor griffithsin and validation of its safety and efficacy as a topical microbicide component. Proc. Natl. Acad. Sci. USA. 2009; 106 (15): 6099–6104. DOI: 10.1073/pnas.0901506106.
36. Di Fabio S., Van Roey J., Giannini G., van den Mooter G., Spada M., Binelli A., Pirillo M.F., Germinario E., Belardelli F., de Bethune M.P., Vella S. Inhibition of vaginal trans-mission of FflV-l in hu-SCID mice by the nonnucleoside reverse transcriptase inhibitor TMC120 in a gel formulation. AIDS. 2003; 17 (11): 1597–1604. DOI: 10.1097/01.aids.0000072663.21517.63.
37. Abdool Karim Q., Abdool Karim S.S., Frohlich J.A., Grobler A.C., Baxter C., Mansoor L.E., Kharsany A.B., Sibeko S., Mlisana K.P., Omar Z., Gengiah T.N., Maarschalk S., Arulappan N., Mlotshwa M., Morris L., Taylor D.; CAPRISA 004 Trial Group. Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science. 2010; 329 (5996): 1168–1174. DOI: 10.1126/science.1193748.
38. Lederman M.M., Veazey R.S., Offord R., Mosier D.E., Dufour J., Mefford M., Piatak M. Jr., Lifson J.D., Salkowitz J.R., Rodriguez B., Blauvelt A., Hartley O. Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science. 2004; 306 (5695): 485–487. DOI: 10.1126/science.1099288.
39. Adlin Jino Nesalina J., Anton Smith A. Preparation and evaluation of chitosan nanoparticles containing zidovudine. Asian. J. Pharm. Sci. 2012; 7 (1): 80-84.
40. Tsai C.C., Emau P., Jiang Y., Agy M.B., Shattock R.J., Schmidt A., Morton W.R., Gustafson K.R., Boyd M.R. Cyanovirin-N inhibits AIDS virus infec-tions in vaginal transmission models. AIDS Res. Hum. Retroviruses. 2004; 20 (1): 11–18. DOI: 10.1089/088922204322749459.
41. Eckstein P., Jackson M.C., Millman N., Sobrero A.J. Comparison of vaginal tolerance tests of spermi-cidal preparations in rabbits and monkeys. J. Reprod. Fertil. 1969; 20 (1): 85–93.
42. Dudek T.E., No D.C., Seung E., Vrbanac V.D., Fadda L., Bhoumik P., Boutwell C.L., Power K.A., Gladden A.D., Battis L., Mellors E.F., Tivey T.R., Gao X., Altfeld M., Luster A.D., Tager A.M., Allen T.M. Rapid Evolution of HIV-1 to Functional CD8+ T Cell Responses in Humanized BLT Mice. Sci. Transl. Med. 2012; 4 (143): 143ra98. DOI: 10.1126/scitranslmed.3003984.
43. Maher D., Wu X., Schacker T., Horbul J., Southern P. HIV binding, penetration, and primary infection in human cervicovaginal tissue. Proc. Natl. Acad. Sci. USA. 2005; 102 (32): 11504–11509. DOI: 10.1073/pnas.0500848102.
44. Cummins J.E. Jr., Guarner J. Flowers L., Guenther P.C., Bartlett J., Morken T., Grohskopf L.A., Paxton L., Dezzutti C.S. Preclinical testing of candidate topical microbicides for anti-human immunodeficiency virus type 1 activity and toxicity in a human cervical explant culture. Antimicrob. Agents Chemother. 2007; 51 (5): 1770–1779. DOI: 10.1128/AAC.01129-06.
45. Lackman-Smith C., Osterling C., Luckenbaugh K., Mankowski M., Snyder B., Lewis G., Paull J., Profy A., Ptak R.G., Buckheit R.W. Jr., Watson K.M., Cummins J.E. Jr., Sanders-Beer B.E. Development of a comprehensive human immunodeficiency virus type 1 screening algorithm for discovery and preclinical testing of topical microbicides. Antimicrob. Agents Chemother. 2008; 52 (5): 1768–1781. DOI: 10.1128/AAC.01328-07.
46. Watson K.M., Buckheit C.E., Buckheit R.W. Jr. Comparative evaluation of virus transmission inhibition by dual-acting pyrimidinedione microbicides using the microbicide transmission and sterilization assay. Antimicrob. Agents Chemother. 2008; 52 (8): 2787–2796. DOI: 10.1128/AAC.01657-07.
Review
For citations:
Zhernov Yu.V., Khaitov M.R. Microbicides for topical immunoprevention of HIV infection. Bulletin of Siberian Medicine. 2019;18(1):49-59. (In Russ.) https://doi.org/10.20538/1682-0363-2019-1-49-59
Views:
1551
Email this article 