Chapter 15 : Microbicides: Molecular Strategies for Prevention of Sexually Transmitted Viral Disease

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This chapter provides an overview on molecular strategies for prevention of sexually transmitted viral disease. The chapter focuses on the perceived need, basic research challenges, and scientific grounds for confidence in the development of anti-human immunodeficiency virus (HIV) type 1 (HIV-1) microbicides with emphasis on viral/pathogen synergies and mucosal factors of susceptibility. Synergistic mechanisms underlying the phenomenon of "amplified transmission" are discussed in the chapter. Mathematical modeling predicts that even a partial protection would substantially relieve the burden of the HIV pandemic. Nevertheless, because of the viral diversity and the complexity and redundancy of the viral mucosal penetration routes, it is unlikely that a single microbicide or multiple microbicides inhibiting acquisition via a single target would prove to be fully efficient. The major mechanisms of action targeted by microbicides, so far, are degrading or neutralizing the virus before it reaches its target cells, blocking the viral entry and intercellular passage, as well as attacking the intra-cellular steps of the viral cycle, mainly the reverse transcription and viral integration processes. The mechanism of action of the antiretroviral drugs nucleoside and non-nucleoside RT inhibitors (NRTIs and NNRTIs) is discussed in detail. The development of prevention strategies and tools to encompass the global diversity of HIV-1, to be holistically compatible with the wide range of age and multicultural and socioeconomic backgrounds, is a colossal international undertaking that has mobilized scientists, advocates, philanthropists, and policy makers around the world.

Citation: Fichorova R. 2009. Microbicides: Molecular Strategies for Prevention of Sexually Transmitted Viral Disease, p 265-282. In LaFemina, Ph. D. R (ed), Antiviral Research. ASM Press, Washington, DC. doi: 10.1128/9781555815493.ch15
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1. Alfano, M., and, G. Poli. 2005. Role of cytokines and chemokines in the regulation of innate immunity and HIV infection. Mol. Immunol. 42:161182.
2. Alfsen, A., and, M. Bomsel. 2002. HIV-1 gp41 envelope residues 650–685 exposed on native virus act as a lectin to bind epithelial cell galactosyl ceramide. J. Biol. Chem. 277:2564925659.
3. Arrighi, J. F.,, C. Soulas,, C. Hauser,, S. Saeland,, B. Chapuis,, R. H. Zubler, and, V. Kindler. 2003. TNF-alpha induces the generation of Langerin/(CD207)+ immature Langerhans-type dendritic cells from both CD14-CD1a and CD14+ CD1a- precursors derived from CD34+ cord blood cells. Eur. J. Immunol. 33:20532063.
4. Ataman-Onal, Y.,, S. Munier,, A. Ganee,, C. Terrat,, P.-Y. Durand,, N. Battail,, F. Martinon,, R. Le Grand,, M.-H. Charles,, T. Delair, and, B. Verrier. 2006. Surfactant-free anionic PLA nanoparticles coated with HIV-1 p24 protein induced enhanced cellular and humoral immune responses in various animal models. J. Control. Release 112:175185.
5. Aynaud, O.,, J. D. Poveda,, B. Huynh,, A. Guillemotonia, and, R. Barrasso. 2002. Frequency of herpes simplex virus, cytomegalo-virus and human papillomavirus DNA in semen. Int. J. STD AIDS 13:547550.
6. Balzarini, J., and, L. Van Damme. 2005. Intravaginal and intrarectal microbicides to prevent HIV infection. CMAJ 172:461464.
7. Balzarini, J., and, L. Van Damme. 2007. Microbicide drug candidates to prevent HIV infection. Lancet 369:787797.
8. Barbes, C., and, S. Boris. 1999. Potential role of lactobacilli as prophylactic agents against genital pathogens. AIDS Patient Care STDs 13:747751.
9. Barnett, S. W.,, I. K. Srivastava,, E. Kan,, F. Zhou,, A. Goodsell,, A. D. Cristillo,, M. G. Ferrai,, D. E. Weiss,, N. L. Letvin,, D. Montefiori,, R. Pal, and, M. Vajdy. 2008. Protection of macaques against vaginal SHIV challenge by systemic or mucosal and systemic vaccinations with HIV-envelope. AIDS 22:339348.
10. Belec, L.,, C. Tevi-Benissan,, A. Bianchi,, S. Cotigny,, M. Beumont-Mauviel,, A. Si-Mohamed, and, J. E. Malkin. 2000. In vitro inactivation of Chlamydia trachomatis and of a panel of DNA (HSV-2, CMV, adenovirus, BK virus) and RNA (RSV, enterovirus) viruses by the spermicide benzalkonium chloride. J. Antimicrob. Che-mother. 46:685693.
11. Bezold, G.,, J. A. Politch,, N. B. Kiviat,, J. M. Kuypers,, H. Wolff, and, D. J. Anderson. 2007. Prevalence of sexually transmissible pathogens in semen from asymptomatic male infertility patients with and without leukocytospermia. Fertil. Steril. 87:10871097.
12. Bezold, G.,, A. Schuster-Grusser,, M. Lange,, H. Gall,, H. Wolff, and, R. U. Peter. 2001. Prevalence of human herpesvirus types 1–8 in the semen of infertility patients and correlation with semen parameters. Fertil. Steril. 76:416418.
13. Bobardt, M. D.,, M. Armand-Ugon,, I. Clotet,, Z. Zhang,, G. David,, J. A. Este, and, P. A. Gallay. 2004. Effect of polyanion-resistance on HIV-1 infection. Virology 325:389398.
14. Bollen, L. J.,, K. Blanchard,, P. H. Kilmarx,, S. Chaikummao,, C. Connolly,, P. Wasinrapee,, N. Srivirojana,, J. Achalapong,, J. W. Tappero, and, J. M. McNicholl. 2008. No increase in cervicovaginal proinflammatory cytokines after Carraguard use in a placebo-controlled randomized clinical trial. J. Acquir. Immune Defic. Syndr. 47:253257.
15. Bomsel, M. 1997. Transcytosis of infectious human immunodeficiency virus across a tight human epithelial cell line barrier. Nat. Med. 3:4247.
16. Carpenter, L. M.,, A. Kamali,, A. Ruberantwari,, S. S. Malamba, and, J. A. Whitworth. 1999. Rates of HIV-1 transmission within marriage in rural Uganda in relation to the HIV sero-status of the partners. AIDS 13:10831089.
17. Catalone, B. J.,, S. R. Miller,, M. L. Ferguson,, D. Malamud,, T. Kish-Catalone,, N. J. Thakkar,, F. C. Krebs,, M. K. Howett, and, B. Wigdahl. 2005. Toxicity, inflammation, and anti-human immunodeficiency virus type 1 activity following exposure to chemical moieties of C31G. Biomed. Pharmacother. 59:430437.
18. Chen, L. 2007. Sexual risk factors for HIV infection in early and advanced HIV epidemics in sub-Saharan Africa: systematic overview of 68 epidemiological studies. PLoS ONE 2:e1001.
19. Clark, S.,, J. Bruce, and, A. Dude. 2006. Protecting young women from HIV/AIDS: the case against child and adolescent marriage. Int. Fam. Plan. Perspect. 32:7988.
20. Cohen, M. S., and, C. D. Pilcher. 2005. Amplified HIV transmission and new approaches to HIV prevention. J. Infect. Dis. 191:13911393.
21. Cole, A. L.,, A. Herasimtschuk,, P. Gupta,, A. J. Waring,, R. I. Lehrer, and, A. M. Cole. 2007. The retrocyclin analogue RC-101 prevents human immunodeficiency virus type 1 infection of a model human cervicovaginal tissue construct. Immunology 121:140145.
22. Cole, A. M. 2006. Innate host defense of human vaginal and cervical mucosae. Curr. Top. Microbiol. Immunol. 306:199230.
23. Cone, R. A.,, T. Hoen,, X. Wong,, R. Abusuwwa,, D. J. Anderson, and, T. R. Moench. 2006. Vaginal microbicides: detecting toxici-ties in vivo that paradoxically increase pathogen transmission. BMC Infect. Dis. 6:90.
24. Cook, W. J.,, M. F. Kramer,, R. M. Walker,, T. J. Burwell,, H. A. Holman,, D. M. Coen, and, D. M. Knipe. 2004. Persistent expression of chemokine and chemokine receptor RNAs at primary and latent sites of herpes simplex virus 1 infection. Virol. J. 1:5.
25. Corey, L.,, A. Wald,, C. L. Celum, and, T. C. Quinn. 2004. The effects of herpes simplex virus-2 on HIV-1 acquisition and transmission: a review of two overlapping epidemics. J. Acquir. Immune. Defic. Syndr. 35:435445.
26. Crawford, D. H.,, A. J. Swerdlow,, C. Higgins,, K. McAulay,, N. Harrison,, H. Williams,, K. Britton, and, K. F. Macsween. 2002. Sexual history and Epstein-Barr virus infection. J. Infect. Dis. 186:731736.
27. Cruz, O. J., and, F. M. Uckun. 2007. Preclinical evaluation of a dual-acting microbicidal prodrug WHI-07 in combination with vanadocene dithiocarbamate in the female reproductive tract of rabbit, pig, and cat. Toxicol. Pathol. 35:910927.
28. Cummins, J. E., Jr.,, J. Guarner,, L. Flowers,, P. C. Guenthner,, J. Bartlett,, T. Morken,, L. A. Grohskopf,, L. Paxton, and, C. S. Dezzutti. 2007. Preclinical testing of candidate topical microbicides for anti-human immunodeficiency virus type 1 activity and tissue toxicity in a human cervical explant culture. Antimicrob. Agents Chemother. 51:17701779.
29. Cu-Uvin, S. 2005. Effect of the menstrual cycle on virological parameters. J. Acquir. Immune. Defic. Syndr. 38(Suppl. 1):S33S34.
30. Daher, K. A.,, M. E. Selsted, and, R. I. Lehrer. 1986. Direct inactivation of viruses by human granulocyte defensins. J. Virol. 60:10681074.
31. D’Cruz, O. J., and, F. M. Uckun. 2006. Dawn of non-nucleoside inhibitor-based anti-HIV microbicides. J. Antimicrob. Chemother. 57:411423.
32. De Clercq, E. 2000. Current lead natural products for the chemo-therapy of human immunodeficiency virus (HIV) infection. Med. Res. Rev. 20:323349.
33. Denton, P. W.,, J. D. Estes,, Z. Sun,, F. A. Othieno,, B. L. Wei,, A. K. Wege,, D. A. Powell,, D. Payne,, A. T. Haase, and, J. V. Garcia. 2008. Antiretroviral pre-exposure prophylaxis prevents vaginal transmission of HIV-1 in humanized BLT mice. PLoS Med. 5:e16.
34. de Witte, L.,, A. Nabatov,, M. Pion,, D. Fluitsma,, M. A. de Jong,, T. de Gruijl,, V. Piguet,, Y. van Kooyk, and, T. B. Geijtenbeek. 2007. Langerin is a natural barrier to HIV-1 transmission by Langerhans cells. Nat. Med. 13:367371.
35. Dezzutti, C. S.,, P. C. Guenthner,, J. E. Cummins, Jr.,, T. Cabrera,, J. H. Marshall,, A. Dillberger, and, R. B. Lal. 2001. Cervical and prostate primary epithelial cells are not productively infected but sequester human immunodeficiency virus type 1. J. Infect. Dis. 183:12041213.
36. Dezzutti, C. S.,, V. N. James,, A. Ramos,, S. T. Sullivan,, A. Siddig,, T. J. Bush,, L. A. Grohskopf,, L. Paxton,, S. Subbarao, and, C. E. Hart. 2004. In vitro comparison of topical microbicides for prevention of human immunodeficiency virus type 1 transmission. Antimicrob. Agents Chemother. 48:38343844.
37. Dhawan, D., and, K. H. Mayer. 2006. Microbicides to prevent HIV transmission: overcoming obstacles to chemical barrier protection. J. Infect. Dis. 193:3644.
38. Doncel, G. F.,, N. Chandra, and, R. N. Fichorova. 2004. Preclinical assessment of the proinflammatory potential of microbicide candidates. J. Acquir. Immune Defic. Syndr. 37(Suppl. 3):S174S180.
39. Eckstein, P.,, M. C. N. Jackson,, N. Millman, and, A. J. Sobrero. 1969. Comparison of vaginal tolerance tests of spermicidal preparations in rabbits and monkeys. J. Reprod. Fertil. 20:8593.
40. Emau, P.,, B. Tian,, B. R. O’Keefe,, T. Mori,, J. B. McMahon,, K. E. Palmer,, Y. Jiang,, G. Bekele, and, C. C. Tsai. 2007. Griffithsin, a potent HIV entry inhibitor, is an excellent candidate for anti-HIV microbicide. J. Med. Primatol. 36:244253.
41. Falagas, M. E.,, G. I. Betsi, and, S. Athanasiou. 2006. Probiotics for prevention of recurrent vulvovaginal candidiasis: a review. J. Antimicrob. Chemother. 58:266272.
42. Feldblum, P. J.,, A. Adeiga,, R. Bakare,, S. Wevill,, A. Lendvay,, F. Obadaki,, M. O. Olayemi,, L. Wang,, K. Nanda, and, W. Rountree. 2008. SAVVY vaginal gel (C31G) for prevention of HIV infection: a randomized controlled trial in Nigeria. PLoS ONE 3:e1474.
43. Fernandez-Romero, J. A.,, M. Thorn,, S. G. Turville,, K. Titchen,, K. Sudol,, J. Li,, T. Miller,, M. Robbiani,, R. A. Maguire,, R. W. Buck-heit, Jr.,, T. L. Hartman, and, D. M. Phillips. 2007. Carrageenan/MIV-150 (PC-815), a combination microbicide. Sex. Transm. Dis. 34:914.
44. Fichorova, R., and, D. Anderson. 1999. Cytokines in the cervical vaginal environment, p. 79–91. In J. A. Hill (ed.), Cytokines in Human Reproduction. Wiley-Liss, New York, NY.
45. Fichorova, R. N. 2004. Guiding the vaginal microbicide trials with biomarkers of inflammation. J. Acquir. Immune Defic. Syndr. 37(Suppl. 3):S184S193.
46. Fichorova, R. N.,, M. Bajpai,, N. Chandra,, J. G. Hsiu,, M. Span-gler,, V. Ratnam, and, G. F. Doncel. 2004. Interleukin (IL)-1, IL-6, and IL-8 predict mucosal toxicity of vaginal microbicidal contraceptives. Biol. Reprod. 71:761769.
47. Fichorova, R. N.,, L. D. Tucker, and, D. J. Anderson. 2001. The molecular basis of nonoxynol-9-induced vaginal inflammation and its possible relevance to human immunodeficiency virus type 1 transmission. J. Infect. Dis. 184:418428.
48. Fichorova, R. N.,, F. Zhou,, V. Ratnam,, V. Atanassova,, S. Jiang,, N. Strick, and, A. R. Neurath. 2005. Anti-human immunodeficiency virus type 1 microbicide cellulose acetate 1,2-benzenedicarboxylate in a human in vitro model of vaginal inflammation. Antimicrob. Agents Chemother. 49:323335.
49. Finnegan, C., and, R. Blumenthal. 2006. Dissecting HIV fusion: identifying novel targets for entry inhibitors. Infect. Disord. Drug Targets 6:355367.
50. Fletcher, P. S.,, S. J. Harman,, A. R. Boothe,, G. F. Doncel, and, R. J. Shattock. 2008. Preclinical evaluation of lime juice as a topical microbicide candidate. Retrovirology 5:3.
51. Fletcher, P. S.,, G. S. Wallace,, P. M. Mesquita, and, R. J. Shattock. 2006. Candidate polyanion microbicides inhibit HIV-1 infection and dissemination pathways in human cervical explants. Retrovirology 3:46.
52. Foster, J. R. 2001. The functions of cytokines and their uses in toxicology. Int. J. Exp. Pathol. 82:171192.
53. Galen, B. T.,, A. P. Martin,, E. Hazrati,, A. Garin,, E. Guzman,, S. S. Wilson,, D. D. Porter,, S. A. Lira,, M. J. Keller, and, B. C. Herold. 2007. A comprehensive murine model to evaluate topical vaginal microbicides: mucosal inflammation and susceptibility to genital herpes as surrogate markers of safety. J. Infect. Dis. 195:13321339.
54. Garg, S.,, R. A. Anderson,, C. J. Chany II,, D. P. Waller,, X. H. Diao,, K. Vermani, and, L. J. Zaneveld. 2001. Properties of a new acid-buffering bioadhesive vaginal formulation (ACIDFORM). Contraception 64:6775.
55. Geijtenbeek, T. B.,, D. S. Kwon,, R. Torensma,, S. J. van Vliet,, G. C. van Duijnhoven,, J. Middel,, I. L. Cornelissen,, H. S. Nottet,, V. N. KewalRamani,, D. R. Littman,, C. G. Figdor, and, Y. van Kooyk. 2000. DC-SIGN, a dendritic cell-specific HIV-1-binding protein that enhances trans-infection of T cells. Cell 100:587597.
56. Gimble, J. M.,, E. Duh,, J. M. Ostrove,, H. E. Gendelman,, E. E. Max, and, A. B. Rabson. 1988. Activation of the human immunodeficiency virus long terminal repeat by herpes simplex virus type 1 is associated with induction of a nuclear factor that binds to the NF-kappa B/core enhancer sequence. J. Virol. 62:41044112.
57. Glynn, J. R.,, M. Carael,, B. Auvert,, M. Kahindo,, J. Chege,, R. Musonda,, F. Kaona, and, A. Buve. 2001. Why do young women have a much higher prevalence of HIV than young men? A study in Kisumu, Kenya and Ndola, Zambia. AIDS 15(Suppl. 4):S51S60.
58. Gonczol, E., and, S. Plotkin. 2001. Development of a cytomegalo-virus vaccine: lessons from recent clinical trials. Exp. Opin. Biol. Ther. 1:401412.
59. Hamers-Casterman, C.,, T. Atarhouch,, S. Muyldermans,, G. Robinson,, C. Hamers,, E. B. Songa,, N. Bendahman, and, R. Hamers. 1993. Naturally occurring antibodies devoid of light chains. Nature 363:446448.
60. Harmsen, M. M., and, H. J. De Haard. 2007. Properties, production, and applications of camelid single-domain antibody fragments. Appl. Microbiol. Biotechnol. 77:1322.
61. Hemmerling, A.,, M. Potts,, J. Walsh,, B. Young-Holt,, K. Whaley, and, D. A. Stefanski. 2007. Lime juice as a candidate microbicide? An open-label safety trial of 10% and 20% lime juice used vaginally. J. Womens Health(Larchmont) 16:10411051.
62. Hillier, S. L.,, T. Moench,, R. Shattock,, R. Black,, P. Reichelderfer, and, F. Veronese. 2005. In vitro and in vivo: the story of nonoxynol 9. J. Acquir. Immune Defic. Syndr. 39:18.
63. Imade, G. E.,, A. S. Sagay,, V. A. Onwuliri,, D. Z. Egah,, M. Potts, and, R. V. Short. 2005. Use of lemon or lime juice douches in women in Jos, Nigeria. Sex. Health 2:237239.
64. John, M.,, M. J. Keller,, E. H. Fam,, N. Cheshenko,, K. Hogarty,, A. Kasowitz,, S. Wallenstein,, M. J. Carlucci,, A. C. Tuyama,, W. Lu,, M. E. Klotman,, R. I. Lehrer, and, B. C. Herold. 2005. Cervicovaginal secretions contribute to innate resistance to herpes simplex virus infection. J. Infect. Dis. 192:17311740.
65. Kapranos, N.,, E. Petrakou,, C. Anastasiadou, and, D. Kotronias. 2003. Detection of herpes simplex virus, cytomegalovirus, and Epstein-Barr virus in the semen of men attending an infertility clinic. Fertil. Steril. 79(Suppl. 3):15661570.
66. Keller, M. J.,, E. Guzman,, E. Hazrati,, A. Kasowitz,, N. Cheshenko,, S. Wallenstein,, A. L. Cole,, A. M. Cole,, A. T. Profy,, C. R. Wira,, K. Hogarty, and, B. C. Herold. 2007. PRO 2000 elicits a decline in genital tract immune mediators without compromising intrinsic antimicrobial activity. AIDS 21:467476.
67. Keller, M. J.,, B. Zerhouni-Layachi,, N. Cheshenko,, M. John,, K. Hogarty,, A. Kasowitz,, C. L. Goldberg,, S. Wallenstein,, A. T. Profy,, M. E. Klotman, and, B. C. Herold. 2006. PRO 2000 gel inhibits HIV and herpes simplex virus infection following vaginal application: a double-blind placebo-controlled trial. J. Infect. Dis. 193:2735.
68. Kish-Catalone, T.,, R. Pal,, J. Parrish,, N. Rose,, L. Hocker,, L. Hudacik,, M. Reitz,, R. Gallo, and, A. Devico. 2007. Evaluation of -2 RANTES vaginal microbicide formulations in a nonhuman primate simian/human immunodeficiency virus (SHIV) challenge model. AIDS Res. Hum. Retrovir. 23:3342.
69. Klasse, P. J.,, R. Shattock, and, J. P. Moore. 2007. Antiretroviral drug-based microbicides to prevent HIV-1 sexual transmission. Annu. Rev. Med. 59:455471.
70. Kozlowski, P. A.,, S. Cu-Uvin,, M. R. Neutra, and, T. P. Flanigan. 1999. Mucosal vaccination strategies for women. J. Infect. Dis. 179(Suppl. 3):S493S498.
71. Lard-Whiteford, S. L.,, D. Matecka,, J. O’Rear,, I. S. Yuen,, C. Litterst, and, P. Reichelderfer. 2004. Recommendations for the non-clinical development of topical microbicides for prevention of HIV transmission: an update. J. Acquir. Immune Defic. Syndr. 36:541552.
72. Lederman, M. M.,, R. E. Offord, and, O. Hartley. 2006. Microbicides and other topical strategies to prevent vaginal transmission of HIV. Nat. Rev. Immunol. 6:371382.
73. Lederman, M. M.,, A. Penn-Nicholson,, M. Cho, and, D. Mosier. 2006. Biology of CCR5 and its role in HIV infection and treatment. JAMA 296:815826.
74. Leikina, E.,, H. Delanoe-Ayari,, K. Melikov,, M. S. Cho,, A. Chen,, A. J. Waring,, W. Wang,, Y. Xie,, J. A. Loo,, R. I. Lehrer, and, L. V. Chernomordik. 2005. Carbohydrate-binding molecules inhibit viral fusion and entry by crosslinking membrane glycoproteins. Nat. Immunol. 6:9951001.
75. Leonard, J. T., and, K. Roy. 2006. The HIV entry inhibitors revisited. Curr. Med. Chem. 13:911934.
76. Liu, S.,, H. Lu,, A. R. Neurath, and, S. Jiang. 2005. Combination of candidate microbicides cellulose acetate 1,2-benzenedicarboxylate and UC781 has synergistic and complementary effects against human immunodeficiency virus type 1 infection. Antimicrob. Agents Chemother. 49:18301836.
77. Liu, S.,, S. Wu, and, S. Jiang. 2007. HIV entry inhibitors targeting gp41: from polypeptides to small-molecule compounds. Curr. Pharm. Des. 13:143162.
78. Liu, X.,, L. A. Lagenaur,, D. A. Simpson,, K. P. Essenmacher,, C. L. Frazier-Parker,, Y. Liu,, D. Tsai,, S. S. Rao,, D. H. Hamer,, T. P. Parks,, P. P. Lee, and, Q. Xu. 2006. Engineered vaginal lactobacillus strain for mucosal delivery of the human immunodeficiency virus inhibitor cyanovirin-N. Antimicrob. Agents Chemother. 50:32503259.
79. Lurain, N. S.,, E. S. Robert,, J. Xu,, M. Camarca,, A. Landay,, A. A. Kovacs, and, P. S. Reichelderfer. 2004. HIV type 1 and cytomegalovirus coinfection in the female genital tract. J. Infect. Dis. 190:619623.
80. Madan, R. P.,, P. M. M. Mesquita,, N. Cheshenko,, B. Jing,, V. Shende,, E. Guzman,, T. Heald,, M. J. Keller,, S. L. Regen,, R. J. Shattock, and, B. C. Herold. 2007. Molecular umbrellas: a novel class of candidate topical microbicides to prevent human immunodeficiency virus and herpes simplex virus infections. J. Virol. 81:76367646.
81. Mauck, C. K.,, S. A. Ballagh,, M. D. Creinin,, D. H. Weiner,, G. F. Doncel,, R. N. Fichorova,, J. L. Schwartz,, N. Chandra, and, M. M. Callahan. 2008. Six-day randomized safety trial of intravaginal lime juice. J. Acquir. Immune Defic. Syndr. 49:243250.
82. Mayer, K. H.,, L. A. Maslankowski,, F. Gai,, W. M. El-Sadr,, J. Just-man,, A. Kwiecien,, B. Mâsse,, S. H. Eshleman,, C. Hendrix,, K. Morrow,, J. F. Rooney,, L. Soto-Torres, et al. 2006. Safety and tolerability of tenofovir vaginal gel in abstinent and sexually active HIV-infected and uninfected women. AIDS 20:543551.
83. McCarthy, T. D.,, P. Karellas,, S. A. Henderson,, M. Giannis,, D. F. O’Keefe,, G. Heery,, J. R. A. Paull,, B. R. Matthews, and, G. Holan. 2005. Dendrimers as drugs: discovery and preclinical and clinical development of dendrimer-based microbicides for HIV and STI prevention. Mol. Pharm. 2:312318.
84. McCoombe, S. G., and, R. V. Short. 2006. Potential HIV-1 target cells in the human penis. AIDS 20:14911495.
85. McGowan, I.,, J. Elliott,, G. Cortina,, K. Tanner,, C. Siboliban,, A. Adler,, D. Cho,, W. J. Boscardin,, L. Soto-Torres, and, P. A. Anton. 2007. Characterization of baseline intestinal mucosal indices of injury and inflammation in men for use in rectal microbicide trials (HIV Prevention Trials Network-056). J. Acquir. Immune Defic. Syndr. 46:417425.
86. McNeely, T. B.,, M. Dealy,, D. J. Dripps,, J. M. Orenstein,, S. P. Eisenberg, and, S. M. Wahl. 1995. Secretory leukocyte protease inhibitor: a human saliva protein exhibiting anti-human immunodeficiency virus 1 activity in vitro. J. Clin. Investig. 96:456464.
87. Msellati, P.,, N. Meda,, V. Leroy,, R. Likikouet,, P. Van de Perre,, M. Cartoux,, D. Bonard,, A. Ouangre,, P. Combe,, L. Gautier-Char-pentier,, F. Sylla-Koko,, R. Lassalle,, M. Dosso,, C. Welffens-Ekra,, F. Dabis,, L. Mandelbrot, et al. 1999. Safety and acceptability of vaginal disinfection with benzalkonium chloride in HIV infected pregnant women in west Africa: ANRS 049b phase II randomized, double blinded placebo controlled trial. Sex. Transm. Infect. 75:420425.
88. Nagot, N.,, A. Ouedraogo,, V. Foulongne,, I. Konate,, H. A. Weiss,, L. Vergne,, M.-C. Defer,, D. Djagbare,, A. Sanon,, J.-B. Andonaba,, P. Becquart,, M. Segondy,, R. Vallo,, A. Sawadogo,, P. Van de Perre,, P. Mayaud, et al. 2007. Reduction of HIV-1 RNA levels with therapy to suppress herpes simplex virus. N. Engl. J. Med. 356:790799.
89. Neurath, A. R.,, N. Strick, and, Y. Y. Li. 2002. Anti-HIV-1 activity of anionic polymers: a comparative study of candidate microbicides. BMC Infect. Dis. 2:27.
90. Neurath, A. R.,, N. Strick, and, Y. Y. Li. 2006. Role of seminal plasma in the anti-HIV-1 activity of candidate microbicides. BMC Infect. Dis. 6:150.
91. Newell, M. L. 1998. Mechanisms and timing of mother-to-child transmission of HIV-1. AIDS 12:831837.
92. Newell, M. L., and, T. Barnighausen. 2007. Male circumcision to cut HIV risk in the general population. Lancet 369:617619.
93. O’Neil, L. A., and, C. Greene. 1998. Signal transduction pathways activated by the IL-1 receptor family: ancient signaling machinery in mammals, insects and plants. J. Leukoc. Biol. 63:650657.
94. Pant, N.,, A. Hultberg,, Y. Zhao,, L. Svensson,, Q. Pan-Hammar-strom,, K. Johansen,, P. H. Pouwels,, F. M. Ruggeri,, P. Hermans,, L. Frenken,, T. Boren,, H. Marcotte, and, L. Hammarstrom. 2006. Lactobacilli expressing variable domain of llama heavy-chain antibody fragments (lactobodies) confer protection against rotavirus-induced diarrhea. J. Infect. Dis. 194:15801588.
95. Patel, S.,, E. Hazrati,, N. Cheshenko,, B. Galen,, H. Yang,, E. Guzman,, R. Wang,, B. C. Herold, and, M. J. Keller. 2007. Seminal plasma reduces the effectiveness of topical polyanionic microbicides. J. Infect. Dis. 196:13941402.
96. Patton, D. L.,, Y. T. Sweeney,, J. E. Balkus,, L. C. Rohan,, B. J. Moncla,, M. A. Parniak, and, S. L. Hillier. 2007. Preclinical safety assessments of UC781 anti-human immunodeficiency virus topical microbicide formulations. Antimicrob. Agents Chemother. 51:16081615.
97. Presta, L. G. 2006. Engineering of therapeutic antibodies to minimize immunogenicity and optimize function. Adv. Drug Deliv. Rev. 58:640656.
98. Pudney, J.,, A. J. Quayle, and, D. J. Anderson. 2005. Immunological microenvironments in the human vagina and cervix: mediators of cellular immunity are concentrated in the cervical transformation zone. Biol. Reprod. 73:12531263.
99. Pusch, O.,, D. Boden,, S. Hannify,, F. Lee,, L. Tucker,, M. Boyd,, J. Wells, and, B. Ramratnam. 2005. Bioengineering lactic acid bacteria to secrete the HIV-1 virucide cyanovirin. J. Acquir. Immune Defic. Syndr. 40:512520.
100. Ramachandran, S., and, P. R. Kinchington. 2007. Potential prophylactic and therapeutic vaccines for HSV infections. Curr. Pharm. Des. 13:19651973.
101. Ramjee, G.,, R. Govinden,, N. S. Morar, and, A. Mbewu. 2007. South Africa’s experience of the closure of the cellulose sulphate microbicide trial. PLoS Med. 4:e235.
102. Rebbapragada, A.,, C. Wachihi,, C. Pettengell,, S. Sunderji,, S. Huibner,, W. Jaoko,, B. Ball,, K. Fowke,, T. Mazzulli,, F. A. Plummer, and, R. Kaul. 2007. Negative mucosal synergy between Herpes simplex type 2 and HIV in the female genital tract. AIDS 21:589598.
103. Rollins, B. J. 1997. Chemokines. Blood 90:909928.
104. Scala, G.,, I. Quinto,, M. R. Ruocco,, M. Mallardo,, C. Ambrosino,, B. Squitieri,, P. Tassone, and, S. Venuta. 1993. Epstein-Barr virus nuclear antigen 2 transactivates the long terminal repeat of human immunodeficiency virus type 1. J. Virol. 67:28532861.
105. Schito, M. L.,, A. C. Soloff,, D. Slovitz,, A. Trichel,, J. K. Inman,, E. Appella,, J. A. Turpin, and, S. M. Barratt-Boyes. 2006. Preclinical evaluation of a zinc finger inhibitor targeting lentivirus nucleocapsid protein in SIV-infected monkeys. Curr. HIV Res. 4:379386.
106. Schwartz, J. L.,, C. Mauck,, J. J. Lai,, M. D. Creinin,, V. Brache,, S. A. Ballagh,, D. H. Weiner,, S. L. Hillier,, R. N. Fichorova, and, M. Callahan. 2006. Fourteen-day safety and acceptability study of 6% cellulose sulfate gel: a randomized double-blind Phase I safety study. Contraception 74:133140.
107. Scordi-Bello, I. A.,, A. Mosoian,, C. He,, Y. Chen,, Y. Cheng,, G. A. Jarvis,, M. J. Keller,, K. Hogarty,, D. P. Waller,, A. T. Profy,, B. C. Herold, and, M. E. Klotman. 2005. Candidate sulfonated and sulfated topical microbicides: comparison of anti-human immunodeficiency virus activities and mechanisms of action. Antimicrob. Agents Chemother. 49:36073615.
108. Sekaly, R.-P. 2008. The failed HIV Merck vaccine study: a step back or a launching point for future vaccine development? J. Exp. Med. 205:712.
109. Sen, P., and, S. E. Barton. 2007. Genital herpes and its management. BMJ 334:10481052.
110. Sha, B. E.,, M. R. Zariffard,, Q. J. Wang,, H. Y. Chen,, J. Bremer,, M. H. Cohen, and, G. T. Spear. 2005. Female genital-tract HIV load correlates inversely with Lactobacillus species but positively with bacterial vaginosis and Mycoplasma hominis. J. Infect. Dis. 191:2532.
111. Simon, V.,, D. D. Ho, and, Q. Abdool Karim. 2006. HIV/AIDS epidemiology, pathogenesis, prevention, and treatment. Lancet 368:489504.
112. Sodora, D. L.,, A. Gettie,, C. J. Miller, and, P. A. Marx. 1998. Vaginal transmission of SIV: assessing infectivity and hormonal influences in macaques inoculated with cell-free and cell-associated viral stocks. AIDS Res. Hum. Retrovir. 14(Suppl. 1):S119S123.
113. Sodora, D. L.,, F. Lee,, P. J. Dailey, and, P. A. Marx. 1998. A genetic and viral load analysis of the simian immunodeficiency virus during the acute phase in macaques inoculated by the vaginal route. AIDS Res. Hum. Retrovir. 14:171181.
114. Stanberry, L. R. 2004. Clinical trials of prophylactic and therapeutic herpes simplex virus vaccines. Herpes 11(Suppl. 3):161A169A.
115. Sugawara, T.,, R. M. Gallucci,, P. P. Simeonova, and, M. I. Luster. 2001. Regulation and role of interleukin 6 in wounded human epithelial keratinocytes. Cytokine 15:328336.
116. Szajewska, H. 2007. Probiotics and prebiotics in pediatrics: where are we now? Turk. J. Pediatr. 49:231244.
117. Tao, J.,, Q. Hu,, J. Yang,, R. Li,, X. Li,, C. Lu,, C. Chen,, L. Wang,, R. Shattock, and, K. Ben. 2007. In vitro anti-HIV and -HSV activity and safety of sodium rutin sulfate as a microbicide candidate. Antivir. Res. 75:227233.
118. Tergaonkar, V. 2006. NF[kappa]B pathway: a good signaling paradigm and therapeutic target. Int. J. Biochem. Cell Biol. 38:16471653.
119. Tevi-Benissan, C.,, M. Makuva,, A. Morelli,, M. C. Georges-Courbot,, M. Matta,, A. Georges, and, L. Belec. 2000. Protection of cynomolgus macaque against cervicovaginal transmission of SIVmac251 by the spermicide benzalkonium chloride. J. Acquir. Immune Defic. Syndr. 24:147153.
120. Trifonova, R. T.,, M. Bajpai,, J. M. Pasicznyk,, N. Chandra,, G. F. Doncel, and, R. N. Fichorova. 2007. Biomarkers of leukocyte traffic and activation in the vaginal mucosa. Biomarkers 12:608622.
121. Trifonova, R. T.,, J. M. Pasicznyk, and, R. N. Fichorova. 2006. Biocompatibility of solid-dosage forms of anti-human immunodeficiency virus type 1 microbicides with the human cervicovaginal mucosa modeled ex vivo. Antimicrob. Agents Chemother. 50:40054010.
122. Turner, A. N.,, C. S. Morrison,, N. S. Padian,, J. S. Kaufman,, R. A. Salata,, T. Chipato,, F. A. Mmiro,, R. D. Mugerwa,, F. M. Behets, and, W. C. Miller. 2007. Men’s circumcision status and women’s risk of HIV acquisition in Zimbabwe and Uganda. AIDS 21:17791789.
123. Turpin, J. A.,, M. L. Schito,, L. M. Miller Jenkins,, J. K. Inman,, E. Appella, and, J. Kuan-Teh. 2008. Topical microbicides: a promising approach for controlling the AIDS pandemic via retroviral zinc finger inhibitors. Adv. Pharmacol. 56:229256.
124. UNAIDS. 2006. UNAIDS Global Facts and Figures 2006. http://data.unaids.org/pub/GlobalReport/2006/200605-FS_globalfacts figures_en.pdf.
125. UNAIDS/WHO. 2006. AIDS Epidemic Update 2006. http://data.unaids.org/pub/EpiReport/2006/2006_EpiUpdate_en.pdf.
126. UNAIDS/WHO. 2007. WHO Multi-country Study on Women’s Health and Domestic Violence against Women. http://www.who.int/gender/violence/who_multicountry_study/en/index.html.
127. UNPFA. 2005. The Promise of Equality: Gender Equity, Reproductive Health and the Millennium Development Goals. United Nations Population Fund. http://www.unfpa.org/swp/2005/english/ch1/index.htm.
128. van Baarle, D.,, E. Hovenkamp,, N. H. Dukers,, N. Renwick,, M. J. Kersten,, J. Goudsmit,, R. A. Coutinho,, F. Miedema, and, M. H. van Oers. 2000. High prevalence of Epstein-Barr virus type 2 among homosexual men is caused by sexual transmission. J. Infect. Dis. 181:20452049.
129. Veazey, R. S.,, R. J. Shattock,, M. Pope,, J. C. Kirijan,, J. Jones,, Q. Hu,, T. Ketas,, P. A. Marx,, P. J. Klasse,, D. R. Burton, and, J. P. Moore. 2003. Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nat. Med. 9:343.
130. Vlach, J., and, P. M. Pitha. 1993. Differential contribution of herpes simplex virus type 1 gene products and cellular factors to the activation of human immunodeficiency virus type 1 provirus. J. Virol. 67:44274431.
131. Wallace, A. R.,, A. Teitelbaum,, L. Wan,, M. G. Mulima,, L. Guichard,, S. Skiler,, H. Vilakazi,, F. S. Mapula,, J. Rossier,, S. N. Govender,, P. Lahteenmaki,, R. A. Maguire, and, D. M. Phillips. 2007. Determining the feasibility of utilizing the microbicide applicator compliance assay for use in clinical trials. Contraception 76:5356.
132. WHO. 2007. Microbicides. http://www.who.int/hiv/topics/microbicides/microbicides/en/.
133. Wilkinson, D.,, M. Tholandi,, G. Ramjee, and, G. W. Rutherford. 2002. Nonoxynol-9 spermicide for prevention of vaginally acquired HIV and other sexually transmitted infections: systematic review and meta-analysis of randomised controlled trials including more than 5000 women. Lancet Infect. Dis. 2:613617.
134. Wiysonge, C. S.,, M. S. Shey,, J. Shang,, E. J. Kongnyuy, and, P. Brocklehurst. 2007. Vaginal microbicides for preventing mother-to-child transmission of HIV infection—no evidence of an effect or evidence of no effect? S. Afr. Med. J. 97:530533.
135. Wu, Z.,, Z. Chen, and, D. M. Phillips. 2003. Human genital epithelial cells capture cell-free human immunodeficiency virus type 1 and transmit the virus to CD4+ cells: implications for mechanisms of sexual transmission. J. Infect. Dis. 188:14731482.
136. Xin, J.,, C. Ying,, J. Faro,, H. Gewurz,, J. Bremer, and, G. T. Spear. 2006. Interaction of human immunodeficiency virus (HIV) gly-cans with lectins of the human immune system. Curr. Protein Peptide Sci. 7:317324.
137. Yasin, B.,, W. Wang,, M. Pang,, N. Cheshenko,, T. Hong,, A. J. Waring,, B. C. Herold,, E. A. Wagar, and, R. I. Lehrer. 2004. Theta defensins protect cells from infection by herpes simplex virus by inhibiting viral adhesion and entry. J. Virol. 78:51475156.
138. Yeaman, G. R.,, S. Asin,, S. Weldon,, D. J. Demian,, J. E. Collins,, J. L. Gonzalez,, C. R. Wira,, M. W. Fanger, and, A. L. Howell. 2004. Chemokine receptor expression in the human ectocervix: implications for infection by the human immunodeficiency virus-type I. Immunology 113:524533.
139. Yeaman, G. R.,, A. L. Howell,, S. Weldon,, D. J. Demian,, J. E. Collins,, D. M. O’Connell,, S. N. Asin,, C. R. Wira, and, M. W. Fanger. 2003. Human immunodeficiency virus receptor and coreceptor expression on human uterine epithelial cells: regulation of expression during the menstrual cycle and implications for human immunodeficiency virus infection. Immunology 109:137146.
140. Zaneveld, L. J. D.,, D. P. Waller,, R. A. Anderson,, C. Chany Ii,, W. F. Rencher,, K. Feathergill,, X.-H. Diao,, G. F. Doncel,, B. Herold, and, M. Cooper. 2002. Efficacy and safety of a new vaginal contraceptive antimicrobial formulation containing high molecular weight poly(sodium 4-styrenesulfonate). Biol. Reprod. 66:886894.
141. Zeerleder, S.,, T. Mauron,, B. Lammle, and, W. A. Wuillemin. 2002. Effect of low-molecular weight dextran sulfate on coagulation and platelet function tests. Thrombosis Res. 105:441446.
142. Zhang, C.,, H. Buchanan,, W. Andrews,, A. Evans, and, R. F. Pass. 2006. Detection of cytomegalovirus infection during a vaccine clinical trial in healthy young women: seroconversion and viral shedding. J. Clin. Virol. 35:338342.
143. Zhang, L.,, W. Yu,, T. He,, J. Yu,, R. E. Caffrey,, E. A. Dalmasso,, S. Fu,, T. Pham,, J. Mei,, J. J. Ho,, W. Zhang,, P. Lopez, and, D. D. Ho. 2002. Contribution of human alpha-defensin 1, 2, and 3 to the anti-HIV-1 activity of CD8 antiviral factor. Science 298:9951000.

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