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Advances in the Development of Microbicides for the Prevention of HIV Infection

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Abstract

Microbicides are products that can be applied to vaginal or rectal mucosa with the intent of preventing, or at least significantly reducing, the transmission of sexually transmitted infections, including HIV-1. The past 2 or 3 years of microbicide research have generated several disappointments. Large, phase 2B/3 studies failed to demonstrate product efficacy, were stopped prematurely for futility, and in the worst-case scenario possibly demonstrated microbicide-induced harm. The most recently completed efficacy study (HPTN-035) did not reach statistical significance, but did show that use of PRO-2000 was associated with a 30% reduction in HIV acquisition. Current research focuses on much more potent targeted therapy, including reverse transcriptase inhibitors and CCR5 antagonists. Ongoing challenges include optimizing the identification of safety signals in phase 1/2 studies, defining a rationale for advancing products into efficacy studies, and identifying populations with adequate HIV seroincidence rates for these studies.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Shattock RJ, Moore JP: Inhibiting sexual transmission of HIV-1 infection. Nat Rev Microbiol 2003, 1:25–34.

    Article  CAS  PubMed  Google Scholar 

  2. Hu J, Gardner MB, Miller CJ: Simian immunodeficiency virus rapidly penetrates the cervicovaginal mucosa after intravaginal inoculation and infects intraepithelial dendritic cells. J Virol 2000, 74:6087–6095.

    Article  CAS  PubMed  Google Scholar 

  3. • Li Q, Estes JD, Schlievert PM, et al.: Glycerol monolaurate prevents mucosal SIV transmission. Nature 2009, 458:1034–1038. This unique paper describes the initial immunologic and virologic events in SIV infection, including chemokine-induced early recruitment of target cells to amplify mucosal infection. The authors also demonstrate the use of glycerol monolaurate to circumvent this process.

    Article  CAS  PubMed  Google Scholar 

  4. Mori T, Boyd MR: Cyanovirin-N, a potent human immunodeficiency virus-inactivating protein, blocks both CD4-dependent and CD4-independent binding of soluble gp120 (sgp120) to target cells, inhibits sCD4-induced binding of sgp120 to cell-associated CXCR4, and dissociates bound sgp120 from target cells. Antimicrob Agents Chemother 2001, 45:664–672.

    Article  CAS  PubMed  Google Scholar 

  5. Bewley CA, Otero-Quintero S: The potent anti-HIV protein cyanovirin-N contains two novel carbohydrate binding sites that selectively bind to Man(8) D1D3 and Man(9) with nanomolar affinity: implications for binding to the HIV envelope protein gp120. J Am Chem Soc 2001, 123:3892–3902.

    Article  CAS  PubMed  Google Scholar 

  6. Bewley CA: Rapid validation of the overall structure of an internal domain-swapped mutant of the anti-HIV protein cyanovirin-N using residual dipolar couplings. J Am Chem Soc 2001, 123:1014–1015.

    Article  CAS  PubMed  Google Scholar 

  7. Tsai CC, Emau P, Jiang Y, et al.: Cyanovirin-N gel as a topical microbicide prevents rectal transmission of SHIV89.6P in macaques. AIDS Res Hum Retroviruses 2003, 19:535–541.

    Article  CAS  PubMed  Google Scholar 

  8. Tsai CC, Emau P, Jiang Y, et al.: Cyanovirin-N inhibits AIDS virus infections in vaginal transmission models. AIDS Res Hum Retroviruses 2004, 20:11–18.

    Article  CAS  PubMed  Google Scholar 

  9. Pusch O, Boden D, Hannify S, et al.: Bioengineering lactic acid bacteria to secrete the HIV-1 virucide cyanovirin. J Acquir Immune Defic Syndr 2005, 40:512–520.

    Article  CAS  PubMed  Google Scholar 

  10. Sexton A, Drake PM, Mahmood N, et al.: Transgenic plant production of cyanovirin-N, an HIV microbicide. FASEB J 2006, 20:356–358.

    CAS  PubMed  Google Scholar 

  11. Sexton A, Harman S, Shattock RJ, Ma JK: Design, expression, and characterization of a multivalent, combination HIV microbicide. FASEB J 2009, 23:3590–3600.

    Article  CAS  PubMed  Google Scholar 

  12. O’Keefe BR, Vojdani F, Buffa V, et al.: Scaleable manufacture of HIV-1 entry inhibitor griffithsin and validation of its safety and efficacy as a topical microbicide component. Proc Natl Acad Sci U S A 2009, 106:6099–6104.

    Article  PubMed  Google Scholar 

  13. Torre VS, Marozsan AJ, Albright JL, et al.: Variable sensitivity of CCR5-tropic human immunodeficiency virus type 1 isolates to inhibition by RANTES analogs. J Virol 2000, 74:4868–4876.

    Article  CAS  PubMed  Google Scholar 

  14. Lederman MM, Veazey RS, Offord R, et al.: Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science 2004, 306:485–487.

    Article  CAS  PubMed  Google Scholar 

  15. • Cerini F, Landay A, Gichinga C, et al.: Chemokine analogues show suitable stability for development as microbicides. J Acquir Immune Defic Syndr 2008, 49:472–476. This article provides a good example of the expanded preclinical evaluation of two PSC-RANTES analogues to determine whether microbicide activity is reduced in relevant biologic matrices (eg, semen and cervicovaginal fluid).

    Article  CAS  PubMed  Google Scholar 

  16. Veazey RS, Ling B, Green LC, et al.: Topically applied recombinant chemokine analogues fully protect macaques from vaginal simian-human immunodeficiency virus challenge. J Infect Dis 2009, 199:1525–1527.

    Article  CAS  PubMed  Google Scholar 

  17. Barnard J, Borkow G, Parniak MA: The thiocarboxanilide nonnucleoside UC781 is a tight-binding inhibitor of HIV-1 reverse transcriptase. Biochemistry 1997, 36:7786–7792.

    Article  CAS  PubMed  Google Scholar 

  18. Borkow G, Salomon H, Wainberg MA, Parniak MA: Attenuated infectivity of HIV type 1 from epithelial cells pretreated with a tight-binding nonnucleoside reverse transcriptase inhibitor. AIDS Res Hum Retroviruses 2002, 18:711–714.

    Article  CAS  PubMed  Google Scholar 

  19. Dezzutti CS, James VN, Ramos A, et al.: In vitro comparison of topical microbicides for prevention of human immunodeficiency virus type 1 transmission. Antimicrob Agents Chemother 2004, 48:3834–3844.

    Article  CAS  PubMed  Google Scholar 

  20. Abner SR, Guenthner PC, Guarner J, et al.: A human colorectal explant culture to evaluate topical microbicides for the prevention of HIV infection. J Infect Dis 2005, 192:1545–1556.

    Article  CAS  PubMed  Google Scholar 

  21. Jiang YH, Emau P, Cairns JS, et al.: SPL7013 gel as a topical microbicide for prevention of vaginal transmission of SHIV89.6P in macaques. AIDS Res Hum Retroviruses 2005, 21:207–213.

    Article  CAS  PubMed  Google Scholar 

  22. Chen MY, Millwood IY, Wand H, et al.: A randomized controlled trial of the safety of candidate microbicide SPL7013 gel when applied to the penis. J Acquir Immune Defic Syndr 2009, 50:375–380.

    Article  CAS  PubMed  Google Scholar 

  23. Rohan LC, Sassi AB: Vaginal drug delivery systems for HIV prevention. AAPS J 2009, 11:78–87.

    Article  CAS  PubMed  Google Scholar 

  24. Romano J, Variano B, Coplan P, et al.: Safety and availability of dapivirine (TMC120) delivered from an intravaginal ring. AIDS Res Hum Retroviruses 2009, 25:483–488.

    Article  CAS  PubMed  Google Scholar 

  25. Jay J, Shukair S, Langheinrich K, et al.: Modulation of viscoelasticity and HIV transport as a function of pH in a reversibly crosslinked hydrogel. Adv Funct Mater 2009, in press.

  26. Cummins JE Jr, Doncel GF: Biomarkers of cervicovaginal inflammation for the assessment of microbicide safety. Sex Transm Dis 2009, 36:S84–S91.

    Article  CAS  PubMed  Google Scholar 

  27. Patel S, Hazrati E, Cheshenko N, et al.: Seminal plasma reduces the effectiveness of topical polyanionic microbicides. J Infect Dis 2007, 196:1394–1402.

    Article  CAS  PubMed  Google Scholar 

  28. •• Mesquita PM, Cheshenko N, Wilson SS, et al.: Disruption of tight junctions by cellulose sulfate facilitates HIV infection: model of microbicide safety. J Infect Dis 2009, 200:599–608. This article provides an important description of a new approach to identify microbicide-induced epithelial toxicity and/or induction of mucosal inflammatory responses. The authors demonstrate that N-9 and cellulose sulfate have the potential cause mucosal damage.

    Article  CAS  PubMed  Google Scholar 

  29. Denton PW, Estes JD, Sun Z, et al.: Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice. PLoS Med 2008, 5:e16.

    Article  PubMed  Google Scholar 

  30. •• Parikh UM, Dobard C, Sharma S, et al.: Complete protection from repeated vaginal simian-human immunodeficiency virus exposures in macaques by a topical gel containing tenofovir alone or with emtricitabine. J Virol 2009, 83:10358–10365. This article shows that tenofovir gel alone is as effective as a combination of tenofovir and emtricitabine (FTC) in preventing vaginal simian-human immunodeficiency virus infection in the repeated low-dose macaque challenge model, and provides an important rationale for the inclusion of both single and dual RT inhibitor combinations in HIV prevention trials.

    Article  CAS  PubMed  Google Scholar 

  31. Grant RM, Hamer D, Hope T, et al.: Whither or wither microbicides? Science 2008, 321:532–534.

    Article  CAS  PubMed  Google Scholar 

  32. Elliott J, McGowan I, Adler A, et al.: Strong suppression of HIV-1 infection of colorectal explants following in vivo rectal application of UC781 gel: a novel endpoint in a phase I trial [abstract 1067]. Presented at the 16th Conference on Retroviruses and Opportunistic Infections. Montreal, Canada; February 8–11, 2009.

  33. Richardson-Harman N, Lackman-Smith C, Fletcher PS, et al.: Multisite comparison of anti-HIV microbicide activity in explant assays using a novel endpoint analysis. J Clin Microbiol 2009, 47:3530–3539.

    Article  CAS  PubMed  Google Scholar 

  34. Poynten IM, Millwood IY, Falster MO, et al.: The safety of candidate vaginal microbicides since nonoxynol-9: a systematic review of published studies. AIDS 2009, 23:1245–1254.

    Article  CAS  PubMed  Google Scholar 

  35. Hendrix CW, Cao YJ, Fuchs EJ: Topical microbicides to prevent HIV: clinical drug development challenges. Annu Rev Pharmacol Toxicol 2009, 49:349–375.

    Article  CAS  PubMed  Google Scholar 

  36. Dumond JB, Yeh RF, Patterson KB, et al.: Antiretroviral drug exposure in the female genital tract: implications for oral pre- and post-exposure prophylaxis. AIDS 2007, 21:1899–1907.

    Article  CAS  PubMed  Google Scholar 

  37. Dumond JB, Patterson KB, Pecha AL, et al.: Maraviroc concentrates in the cervicovaginal fluid and vaginal tissue of HIV-negative women. J Acquir Immune Defic Syndr 2009, 51:546–553.

    Article  PubMed  Google Scholar 

  38. Van Damme L, Ramjee G, Alary M, et al.: Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial. Lancet 2002, 360:971–977.

    Article  PubMed  Google Scholar 

  39. Peterson L, Nanda K, Opoku BK, et al.: 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:e1312.

    Article  PubMed  Google Scholar 

  40. Feldblum PJ, Adeiga A, Bakare R, et al.: SAVVY vaginal gel (C31G) for prevention of HIV infection: a randomized controlled trial in Nigeria. PLoS ONE 2008, 3:e1474.

    Article  PubMed  Google Scholar 

  41. Skoler-Karpoff S, Ramjee G, Ahmed K, et al.: Efficacy of Carraguard for prevention of HIV infection in women in South Africa: a randomised, double-blind, placebo-controlled trial. Lancet 2008, 372:1977–1987.

    Article  CAS  PubMed  Google Scholar 

  42. Van Damme L, Govinden R, Mirembe FM, et al.: Lack of effectiveness of cellulose sulfate gel for the prevention of vaginal HIV transmission. N Engl J Med 2008, 359:463–472.

    Article  PubMed  Google Scholar 

  43. Halpern V, Ogunsola F, Obunge O, et al.: Effectiveness of cellulose sulfate vaginal gel for the prevention of HIV infection: results of a phase III trial in Nigeria. PLoS ONE 2008, 3:e3784.

    Article  PubMed  Google Scholar 

  44. Veazey RS, Klasse PJ, Schader SM, et al.: Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion. Nature 2005, 438:99–102.

    Article  CAS  PubMed  Google Scholar 

  45. Garcia-Lerma JG, Otten RA, Qari SH, et al.: Prevention of rectal SHIV transmission in macaques by daily or intermittent prophylaxis with emtricitabine and tenofovir. PLoS Med 2008, 5:e28.

    Article  PubMed  Google Scholar 

  46. Herrera C, Cranage M, McGowan I, et al.: Reverse transcriptase inhibitors as potential colorectal microbicides. Antimicrob Agents Chemother 2009, 53:1797–1807.

    Article  CAS  PubMed  Google Scholar 

  47. Gorbach PM, Manhart LE, Hess KL, et al.: Anal intercourse among young heterosexuals in three sexually transmitted disease clinics in the United States. Sex Transm Dis 2009, 36:193–198.

    Article  PubMed  Google Scholar 

  48. Kalichman S, Simbayi L, Cain D, Jooste S: Heterosexual anal intercourse among community and clinical settings in Cape Town, South Africa. Sex Transm Infect 2009,85:411–415.

    Article  CAS  PubMed  Google Scholar 

  49. • Baral S, Trapence G, Motimedi F, et al.: HIV prevalence, risks for HIV infection, and human rights among men who have sex with men (MSM) in Malawi, Namibia, and Botswana. PLoS ONE 2009, 4:e4997. This article describes an important epidemiologic study that documents MSM communities in sub-Saharan Africa with high prevalence of HIV infection. These data further strengthen the rationale for the parallel development of rectal and vaginal microbicides.

    Article  PubMed  Google Scholar 

  50. McGowan I: Rectal microbicides: a new focus for HIV prevention. Sex Transm Infect 2008, 84:413–417.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

Dr. McGowan gratefully acknowledges funding from the US National Institutes of Health to support his research in microbicide development (5U19AI060614, 5U01AI066734, and 1R01HD059533).

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No potential conflicts of interest relevant to this article were reported.

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Correspondence to Ian McGowan.

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Minces, L.R., McGowan, I. Advances in the Development of Microbicides for the Prevention of HIV Infection. Curr Infect Dis Rep 12, 56–62 (2010). https://doi.org/10.1007/s11908-009-0076-5

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