Candidate Microbicides and Their Mechanisms of Action

  • Carolina HerreraEmail author
  • Robin J. Shattock
Part of the Current Topics in Microbiology and Immunology book series (CT MICROBIOLOGY, volume 383)


The development of prevention strategies against sexual transmission of human immunodeficiency-1 virus (HIV-1) is essential to curb the rate of new infections. New prevention options include microbicides, many of which are based on antiretroviral (ARV) drugs targeting different stages of the viral replication cycle including: viral entry and fusion; reverse transcription; integration; and viral maturation through proteolytic clevage. In this review, we discuss current and new potential candidate microbicides designed to prevent mucosal HIV acquisition. Preclinical methods, including cellular, tissular, and animal models, used to assess candidate microbicides and evaluate their prioritization for progress through the product development pipeline are reviewed in context with a rapidly evolving clinical landscape.


Simian Immunodeficiency Virus Intervention Point Strand Transfer Viral Replication Cycle CCR5 Inhibitor 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. Abdel-Motal UM, Sarkis PT, Han T, Pudney J, Anderson DJ, Zhu Q, Marasco WA (2011) Anti-gp120 minibody gene transfer to female genital epithelial cells protects against HIV-1 virus challenge in vitro. PLoS One 6:e26473PubMedCentralPubMedGoogle Scholar
  2. Abdool Karim Q, Abdool Karim SS, Frohlich JA, Grobler AC, Baxter C, Mansoor LE, Kharsany AB, Sibeko S, Mlisana KP, Omar Z, Gengiah TN, Maarschalk S, Arulappan N, Mlotshwa M, Morris L, Taylor D (2010) Effectiveness and safety of tenofovir gel, an antiretroviral microbicide, for the prevention of HIV infection in women. Science 329:1168–1174PubMedCentralPubMedGoogle Scholar
  3. Abner SR, Guenthner PC, Guarner J, Hancock KA, Cummins JE Jr, Fink A, Gilmore GT, Staley C, Ward A, Ali O, Binderow S, Cohen S, Grohskopf LA, Paxton L, Hart CE, Dezzutti CS (2005) A human colorectal explant culture to evaluate topical microbicides for the prevention of HIV infection. J Infect Dis 192:1545–1556PubMedGoogle Scholar
  4. Anton P, Cranston R, Carballo-Dieguez A, Kashuba A, Khanukhova E, Elliott J, Janocko L, Cumberland W, Mauck C, McGowan I (2011a) RMP-02/MTN-006: a phase 1 placebo-controlled trial of rectally applied 1 % vaginal TFV gel with comparison to oral TDF. CROI 2011 Google Scholar
  5. Anton PA, Saunders T, Elliott J, Khanukhova E, Dennis R, Adler A, Cortina G, Tanner K, Boscardin J, Cumberland WG, Zhou Y, Ventuneac A, Carballo-Dieguez A, Rabe L, McCormick T, Gabelnick H, Mauck C, McGowan I (2011b) First phase 1 double-blind, placebo-controlled, randomized rectal microbicide trial using UC781 gel with a novel index of ex vivo efficacy. PLoS One 6:e23243PubMedCentralPubMedGoogle Scholar
  6. Arenzana-Seisdedos F, Virelizier JL, Rousset D, Clark-Lewis I, Loetscher P, Moser B, Baggiolini M (1996) HIV blocked by chemokine antagonist. Nature 383:400PubMedGoogle Scholar
  7. Barouch DH, Klasse PJ, Dufour J, Veazey RS, Moore JP (2012) Macaque studies of vaccine and microbicide combinations for preventing HIV-1 sexual transmission. Proc Natl Acad Sci U S A 109:8694–8698PubMedCentralPubMedGoogle Scholar
  8. Berzi A, Reina JJ, Ottria R, Sutkeviciute I, Antonazzo P, Sanchez-Navarro M, Chabrol E, Biasin M, Trabattoni D, Cetin I, Rojo J, Fieschi F, Bernardi A, Clerici M (2012) A glycomimetic compound inhibits DC-SIGN-mediated HIV infection in cellular and cervical explant models. Aids 26:127–137PubMedGoogle Scholar
  9. Broder S (2010) Twenty-five years of translational medicine in antiretroviral therapy: promises to keep. Sci Transl Med 2:39ps33Google Scholar
  10. Buckheit RW Jr, Hartman TL, Watson KM, Chung SG, Cho EH (2008) Comparative evaluation of the inhibitory activities of a series of pyrimidinedione congeners that inhibit human immunodeficiency virus types 1 and 2. Antimicrob Agents Chemother 52:225–236PubMedCentralPubMedGoogle Scholar
  11. Buckheit RW Jr, Watson K, Fliakas-Boltz V, Russell J, Loftus TL, Osterling MC, Turpin JA, Pallansch LA, White EL, Lee JW, Lee SH, Oh JW, Kwon HS, Chung SG, Cho EH (2001) SJ-3366, a unique and highly potent nonnucleoside reverse transcriptase inhibitor of human immunodeficiency virus type 1 (HIV-1) that also inhibits HIV-2. Antimicrob Agents Chemother 45:393–400PubMedCentralPubMedGoogle Scholar
  12. Buckman JS, Bosche WJ, Gorelick RJ (2003) Human immunodeficiency virus type 1 nucleocapsid Zn(2+) fingers are required for efficient reverse transcription, initial integration processes, and protection of newly synthesized viral DNA. J Virol 77:1469–1480PubMedCentralPubMedGoogle Scholar
  13. Burgener A, Boutilier J, Wachihi C, Kimani J, Carpenter M, Westmacott G, Cheng K, Ball TB, Plummer F (2008) Identification of differentially expressed proteins in the cervical mucosa of HIV-1-resistant sex workers. J Proteome Res 7:4446–4454PubMedGoogle Scholar
  14. Burgener A, Rahman S, Ahmad R, Lajoie J, Ramdahin S, Mesa C, Brunet S, Wachihi C, Kimani J, Fowke K, Carr S, Plummer F, Ball TB (2011) Comprehensive proteomic study identifies serpin and cystatin antiproteases as novel correlates of HIV-1 resistance in the cervicovaginal mucosa of female sex workers. J Proteome Res 10:5139–5149PubMedGoogle Scholar
  15. Caron M, Besson G, Etenna SL, Mintsa-Ndong A, Mourtas S, Radaelli A, Morghen Cde G, Loddo R, La Colla P, Antimisiaris SG, Kazanji M (2010) Protective properties of non-nucleoside reverse transcriptase inhibitor (MC1220) incorporated into liposome against intravaginal challenge of Rhesus macaques with RT-SHIV. Virology 405:225–233PubMedGoogle Scholar
  16. Chang TL, Chang CH, Simpson DA, Xu Q, Martin PK, Lagenaur LA, Schoolnik GK, Ho DD, Hillier SL, Holodniy M, Lewicki JA, Lee PP (2003) Inhibition of HIV infectivity by a natural human isolate of Lactobacillus jensenii engineered to express functional two-domain CD4. Proc Natl Acad Sci U S A 100:11672–11677PubMedCentralPubMedGoogle Scholar
  17. Cheng-Mayer C, Huang Y, Gettie A, Tsai L, Ren W, Shakirzyanova M, Sina ST, Trunova N, Blanchard J, Jenkins LM, Lo Y, Schito ML, Appella E (2011) Delay of SHIV infection and control of viral replication in vaccinated macaques challenged in the presence of a topical microbicide. Aids 25:1833-1841 Google Scholar
  18. Collins KB, Patterson BK, Naus GJ, Landers DV, Gupta P (2000) Development of an in vitro organ culture model to study transmission of HIV-1 in the female genital tract. Nat Med 6:475–479PubMedGoogle Scholar
  19. CONRAD (2011) Safety and effectiveness of tenofovir gel in the prevention of human immunodeficiency virus (HIV-1) infection in young women and the effects of tenofovir gel on the incidence of herpes simplex virus (HSV-2) infection.
  20. Cost M, Dezzutti CS, Clark MR, Friend DR, Akil A, Rohan LC (2012) Characterization of UC781–tenofovir combination gel products for HIV-1 infection prevention in an ex vivo ectocervical model. Antimicrob Agents Chemother 56:3058–3066PubMedCentralPubMedGoogle Scholar
  21. Cranage M, Sharpe S, Herrera C, Cope A, Dennis M, Berry N, Ham C, Heeney J, Rezk N, Kashuba A, Anton P, McGowan I, Shattock R (2008) Prevention of SIV rectal transmission and priming of T cell responses in macaques after local pre-exposure application of tenofovir gel. PLoS Med 5:e157PubMedCentralPubMedGoogle Scholar
  22. Crostarosa F, Aravantinou M, Akpogheneta OJ, Jasny E, Shaw A, Kenney J, Piatak M, Lifson JD, Teitelbaum A, Hu L, Chudolij A, Zydowsky TM, Blanchard J, Gettie A, Robbiani M (2009) A macaque model to study vaginal HSV-2/immunodeficiency virus co-infection and the impact of HSV-2 on microbicide efficacy. PLoS One 4:e8060PubMedCentralPubMedGoogle Scholar
  23. Crucitti GC, Botta M, Di Santo R (2012) Will integrase inhibitors be used as microbicides? Curr HIV Res 10:36–41PubMedGoogle Scholar
  24. Cummins JE Jr, Guarner J, Flowers L, Guenthner PC, Bartlett J, Morken T, Grohskopf LA, Paxton L, Dezzutti CS (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 51:1770–1779PubMedCentralPubMedGoogle Scholar
  25. De Clercq E (1998) The role of non-nucleoside reverse transcriptase inhibitors (NNRTIs) in the therapy of HIV-1 infection. Antiviral Res 38:153–179PubMedGoogle Scholar
  26. Dereuddre-Bosquet N, Morellato-Castillo L, Brouwers J, Augustijns P, Bouchemal K, Ponchel G, Ramos OH, Herrera C, Stefanidou M, Shattock R, Heyndrickx L, Vanham G, Kessler P, Le Grand R, Martin L (2012) MiniCD4 microbicide prevents HIV infection of human mucosal explants and vaginal transmission of SHIV(162P3) in cynomolgus macaques. PLoS Pathog 8:: e1003071Google Scholar
  27. Dezzutti CS, James VN, Ramos A, Sullivan ST, Siddig A, Bush TJ, Grohskopf LA, Paxton L, Subbarao S, Hart CE (2004) In vitro comparison of topical microbicides for prevention of human immunodeficiency virus type 1 transmission. Antimicrob Agents Chemother 48:3834–3844PubMedCentralPubMedGoogle Scholar
  28. Dobard C, Sharma S, Martin A, Hazuda D, Hanson DL, Smith J, Otten RA, Novembre FJ, Garcia-Lerma JG, Heneine W (2010) Protection against repeated vaginal SHIV exposures in macaques by a topical gel with an integrase inhibitor. Paper presented at Microbicides 2010, Pittsburgh Google Scholar
  29. Dobard C, Sharma S, Martin A, Pau CP, Holder A, Kuklenyik Z, Lipscomb J, Hanson DL, Smith J, Novembre FJ, Garcia-Lerma JG, Heneine W (2012) Durable protection from vaginal simian–human immunodeficiency virus infection in macaques by tenofovir gel and its relationship to drug levels in tissue. J Virol 86:718–725PubMedCentralPubMedGoogle Scholar
  30. Donahue DA, Sloan RD, Kuhl BD, Bar-Magen T, Schader SM, Wainberg MA (2010) Stage-dependent inhibition of HIV-1 replication by antiretroviral drugs in cell culture. Antimicrob Agents Chemother 54:1047–1054PubMedCentralPubMedGoogle Scholar
  31. Donzella GA, Schols D, Lin SW, Este JA, Nagashima KA, Maddon PJ, Allaway GP, Sakmar TP, Henson G, De Clercq E, Moore JP (1998) AMD3100, a small molecule inhibitor of HIV-1 entry via the CXCR4 co-receptor. Nat Med 4:72–77PubMedGoogle Scholar
  32. Dorr P, Westby M, Dobbs S, Griffin P, Irvine B, Macartney M, Mori J, Rickett G, Smith-Burchnell C, Napier C, Webster R, Armour D, Price D, Stammen B, Wood A, Perros M (2005) Maraviroc (UK-427,857), a potent, orally bioavailable, and selective small-molecule inhibitor of chemokine receptor CCR5 with broad-spectrum anti-human immunodeficiency virus type 1 activity. Antimicrob Agents Chemother 49:4721–4732PubMedCentralPubMedGoogle Scholar
  33. Douville K, Mitchnick M, Baker T, Studebaker D (2006) Modeling phase III microbicide clinical trial costs. Paper presented at AIDS 2006, Toronto Google Scholar
  34. Dragic T, Trkola A, Thompson DA, Cormier EG, Kajumo FA, Maxwell E, Lin SW, Ying W, Smith SO, Sakmar TP, Moore JP (2000) A binding pocket for a small molecule inhibitor of HIV-1 entry within the transmembrane helices of CCR5. Proc Natl Acad Sci U S A 97:5639–5644PubMedCentralPubMedGoogle Scholar
  35. Du T, Hu K, Yang J, Jin J, Li C, Stieh D, Griffin GE, Shattock RJ, Hu Q (2012) Bifunctional CD4-DC-SIGN fusion proteins demonstrate enhanced avidity to gp120 and inhibit HIV-1 infection and dissemination. Antimicrob Agents Chemother 56:4640–4649PubMedCentralPubMedGoogle Scholar
  36. Eade CR, Wood MP, Cole AM (2012) Mechanisms and modifications of naturally occurring host defense peptides for anti-HIV microbicide development. Curr HIV Res 10:61–72PubMedGoogle Scholar
  37. Ejima T, Hirota M, Mizukami T, Otsuka M, Fujita M (2011) An anti-HIV-1 compound that increases steady-state expression of apoplipoprotein B mRNA-editing enzyme-catalytic polypeptide-like 3G. Int J Mol Med 28:613–616PubMedGoogle Scholar
  38. Elinder M, Selhorst P, Vanham G, Oberg B, Vrang L, Danielson UH (2010) Inhibition of HIV-1 by non-nucleoside reverse transcriptase inhibitors via an induced fit mechanism-Importance of slow dissociation and relaxation rates for antiviral efficacy. Biochem Pharmacol 80:1133–1140PubMedGoogle Scholar
  39. Emmelkamp JM, Rockstroh JK (2008) Maraviroc, risks and benefits: a review of the clinical literature. Expert Opin Drug Saf 7:559–569PubMedGoogle Scholar
  40. Engelman A, Mizuuchi K, Craigie R (1991) HIV-1 DNA integration: mechanism of viral DNA cleavage and DNA strand transfer. Cell 67:1211–1221PubMedGoogle Scholar
  41. Evans A, Fletcher P, Herrera C, Shattock RJ (2010) Protease inhibitors darunavir, lopinavir and ritonavir as potential microbicides. Paper presented at Microbicides 2010, Pittsburgh Google Scholar
  42. Fahey JV, Bodwell JE, Hickey DK, Ghosh M, Muia MN, Wira CR (2011) New approaches to making the microenvironment of the female reproductive tract hostile to HIV. Am J Reprod Immunol 65:334–343PubMedGoogle Scholar
  43. Ferir G, Huskens D, Palmer KE, Boudreaux DM, Swanson MD, Markovitz DM, Balzarini J, Schols D (2012) Combinations of griffithsin with other carbohydrate-binding agents demonstrate superior activity against HIV type 1, HIV type 2, and selected carbohydrate-binding agent-resistant HIV type 1 strains. AIDS Res Hum Retroviruses 28:1513-1523 Google Scholar
  44. Figueiredo A, Moore KL, Mak J, Sluis-Cremer N, de Bethune MP, Tachedjian G (2006) Potent nonnucleoside reverse transcriptase inhibitors target HIV-1 Gag-Pol. PLoS Pathog 2:e119PubMedCentralPubMedGoogle Scholar
  45. Fischetti L, Barry SM, Hope TJ, Shattock RJ (2009) HIV-1 infection of human penile explant tissue and protection by candidate microbicides. Aids 23:319–328PubMedGoogle Scholar
  46. Fletcher P, Harman S, Azijn H, Armanasco N, Manlow P, Perumal D, de Bethune MP, Nuttall J, Romano J, Shattock R (2009) Inhibition of human immunodeficiency virus type 1 infection by the candidate microbicide dapivirine, a nonnucleoside reverse transcriptase inhibitor. Antimicrob Agents Chemother 53:487–495PubMedCentralPubMedGoogle Scholar
  47. 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 79:11179–11186PubMedCentralPubMedGoogle Scholar
  48. Fletcher P, Shattock RJ (2008) PRO-2000, an antimicrobial gel for the potential prevention of HIV infection. Curr Opin Invest Drugs 9:189–200Google Scholar
  49. Fletcher PS, Elliott J, Grivel JC, Margolis L, Anton P, McGowan I, Shattock RJ (2006) Ex vivo culture of human colorectal tissue for the evaluation of candidate microbicides. Aids 20:1237–1245PubMedGoogle Scholar
  50. Fogh J, Wright WC, Loveless JD (1977) Absence of HeLa cell contamination in 169 cell lines derived from human tumors. J Natl Cancer Inst 58:209–214PubMedGoogle Scholar
  51. Forsman A, Beirnaert E, Aasa-Chapman MM, Hoorelbeke B, Hijazi K, Koh W, Tack V, Szynol A, Kelly C, McKnight A, Verrips T, de Haard H, Weiss RA (2008) Llama antibody fragments with cross-subtype human immunodeficiency virus type 1 (HIV-1)-neutralizing properties and high affinity for HIV-1 gp120. J Virol 82:12069–12081PubMedCentralPubMedGoogle Scholar
  52. Gaertner H, Cerini F, Escola JM, Kuenzi G, Melotti A, Offord R, Rossitto-Borlat I, Nedellec R, Salkowitz J, Gorochov G, Mosier D, Hartley O (2008) Highly potent, fully recombinant anti-HIV chemokines: reengineering a low-cost microbicide. Proc Natl Acad Sci U S A 105:17706–17711PubMedCentralPubMedGoogle Scholar
  53. Garcia-Perez J, Rueda P, Staropoli I, Kellenberger E, Alcami J, Arenzana-Seisdedos F, Lagane B (2011) New insights into the mechanisms whereby low molecular weight CCR5 ligands inhibit HIV-1 infection. J Biol Chem 286:4978–4990PubMedCentralPubMedGoogle Scholar
  54. Gorlani A, Brouwers J, McConville C, van der Bijl P, Malcolm K, Augustijns P, Quigley AF, Weiss R, De Haard H, Verrips T (2012) Llama antibody fragments have good potential for application as HIV type 1 topical microbicides. AIDS Res Hum Retroviruses 28:198–205PubMedGoogle Scholar
  55. Greenhead P, Hayes P, Watts PS, Laing KG, Griffin GE, Shattock RJ (2000) Parameters of human immunodeficiency virus infection of human cervical tissue and inhibition by vaginal virucides. J Virol 74:5577–5586PubMedCentralPubMedGoogle Scholar
  56. Grivel JC, Elliott J, Lisco A, Biancotto A, Condack C, Shattock RJ, McGowan I, Margolis L, Anton P (2007) HIV-1 pathogenesis differs in rectosigmoid and tonsillar tissues infected ex vivo with CCR5- and CXCR4-tropic HIV-1. Aids 21:1263–1272PubMedGoogle Scholar
  57. Grivel JC, Margolis L (2009) Use of human tissue explants to study human infectious agents. Nat Protoc 4:256–269PubMedCentralPubMedGoogle Scholar
  58. Haase AT (2011) Early events in sexual transmission of HIV and SIV and opportunities for interventions. Annu Rev Med 62:127–139PubMedGoogle Scholar
  59. Harman S, Herrera C, Armanasco N, Nuttall J, Shattock RJ (2012) Preclinical evaluation of the HIV-1 fusion inhibitor L’644 as a potential candidate microbicide. Antimicrob Agents Chemother 56:2347–2356PubMedCentralPubMedGoogle Scholar
  60. Hartley O, Gaertner H, Wilken J, Thompson D, Fish R, Ramos A, Pastore C, Dufour B, Cerini F, Melotti A, Heveker N, Picard L, Alizon M, Mosier D, Kent S, Offord R (2004) Medicinal chemistry applied to a synthetic protein: development of highly potent HIV entry inhibitors. Proc Natl Acad Sci U S A 101:16460–16465PubMedCentralPubMedGoogle Scholar
  61. Herrera C, Armanasco N, King D, Nuttall J, Appella E, Martin L, Kelly C, Shattock RJ (2012) Evaluation of multi-targeting antiretroviral drug combinations as potential microbicides. Paper presented at Microbicides 2012, Sydney Google Scholar
  62. Herrera C, Cranage M, McGowan I, Anton P, Shattock RJ (2009) Reverse transcriptase inhibitors as potential colorectal microbicides. Antimicrob Agents Chemother 53:1797–1807PubMedCentralPubMedGoogle Scholar
  63. Herrera C, Cranage M, McGowan I, Anton P, Shattock RJ (2011) Colorectal microbicide design: triple combinations of reverse transcriptase inhibitors are optimal against HIV-1 in tissue explants. AIDS 25:1971–1979PubMedGoogle Scholar
  64. Herrera C, Shattock RJ (2012) Potential use of protease inhibitors as vaginal and colorectal microbicides. Curr HIV Res 10:42–52PubMedGoogle Scholar
  65. Hillier SL, Moench T, Shattock R, Black R, Reichelderfer P, Veronese F (2005) In vitro and in vivo: the story of nonoxynol 9. J Acq Immune Def Synd 39:1–8Google Scholar
  66. Holt JDS, Nuttall JP (2013) Preclinical safety evaluation. Curr Top Microbiol Immunol.PubMedGoogle Scholar
  67. Hu Q, Frank I, Williams V, Santos JJ, Watts P, Griffin GE, Moore JP, Pope M, Shattock RJ (2004) Blockade of attachment and fusion receptors inhibits HIV-1 infection of human cervical tissue. J Exp Med 199:1065–1075PubMedCentralPubMedGoogle Scholar
  68. Hu Q, Huang X, Shattock RJ (2010) C–C chemokine receptor type 5 (CCR5) utilization of transmitted and early founder human immunodeficiency virus type 1 envelopes and sensitivity to small-molecule CCR5 inhibitors. J Gen Virol 91:2965–2973PubMedCentralPubMedGoogle Scholar
  69. Ingallinella P, Bianchi E, Ladwa NA, Wang YJ, Hrin R, Veneziano M, Bonelli F, Ketas TJ, Moore JP, Miller MD, Pessi A (2009) Addition of a cholesterol group to an HIV-1 peptide fusion inhibitor dramatically increases its antiviral potency. Proc Natl Acad Sci U S A 106:5801–5806PubMedCentralPubMedGoogle Scholar
  70. Johnston SH, Lobritz MA, Nguyen S, Lassen K, Delair S, Posta F, Bryson YJ, Arts EJ, Chou T, Lee B (2009) A quantitative affinity-profiling system that reveals distinct CD4/CCR5 usage patterns among human immunodeficiency virus type 1 and simian immunodeficiency virus strains. J Virol 83:11016–11026PubMedCentralPubMedGoogle Scholar
  71. Jordan R, Gold L, Cummins C, Hyde C (2002) Systematic review and meta-analysis of evidence for increasing numbers of drugs in antiretroviral combination therapy. BMJ 324:757PubMedCentralPubMedGoogle Scholar
  72. Kawamura T, Cohen SS, Borris DL, Aquilino EA, Glushakova S, Margolis LB, Orenstein JM, Offord RE, Neurath AR, Blauvelt A (2000) Candidate microbicides block HIV-1 infection of human immature Langerhans cells within epithelial tissue explants. J Exp Med 192:1491–1500PubMedCentralPubMedGoogle Scholar
  73. Keele BF, Derdeyn CA (2009) Genetic and antigenic features of the transmitted virus. Curr Opin HIV AIDS 4:352–357PubMedGoogle Scholar
  74. Keele BF, Estes JD (2011) Barriers to mucosal transmission of immunodeficiency viruses. Blood 118:839–846PubMedCentralPubMedGoogle Scholar
  75. Kelesidis T, Landovitz RJ (2011) Preexposure prophylaxis for HIV prevention. Curr HIV/AIDS Rep 8:94–103PubMedCentralPubMedGoogle Scholar
  76. Kenney J, Aravantinou M, Singer R, Hsu M, Rodriguez A, Kizima L, Abraham CJ, Menon R, Seidor S, Chudolij A, Gettie A, Blanchard J, Lifson JD, Piatak M Jr, Fernandez-Romero JA, Zydowsky TM, Robbiani M (2011) An antiretroviral/zinc combination gel provides 24 hours of complete protection against vaginal SHIV infection in macaques. PLoS One 6:e15835PubMedCentralPubMedGoogle Scholar
  77. Knechten H, Stephan C, Mosthaf FA, Jaeger H, Carganico A, Lutz T, Schewe K, Mayr C, Wolf E, Wellmann E, Tappe A (2011) The rainbow cohort: 96 week follow-up of saquinavir-containing regimens in previously antiretroviral therapy (ART)-naive and pre-treated but protease inhibitor (PI)-naive HIV-infected patients. Eur J Med Res 16:93–100PubMedCentralPubMedGoogle Scholar
  78. Koh WW, Steffensen S, Gonzalez-Pajuelo M, Hoorelbeke B, Gorlani A, Szynol A, Forsman A, Aasa-Chapman MM, de Haard H, Verrips T, Weiss RA (2010) Generation of a family-specific phage library of llama single chain antibody fragments that neutralize HIV-1. J Biol Chem 285:19116–19124PubMedCentralPubMedGoogle Scholar
  79. Kohl NE, Emini EA, Schleif WA, Davis LJ, Heimbach JC, Dixon RA, Scolnick EM, Sigal IS (1988) Active human immunodeficiency virus protease is required for viral infectivity. Proc Natl Acad Sci U S A 85:4686–4690PubMedCentralPubMedGoogle Scholar
  80. Kondru R, Zhang J, Ji C, Mirzadegan T, Rotstein D, Sankuratri S, Dioszegi M (2008) Molecular interactions of CCR5 with major classes of small-molecule anti-HIV CCR5 antagonists. Mol Pharmacol 73:789–800PubMedGoogle Scholar
  81. Kuramoto H (1972) Studies of the growth and cytogenetic properties of human endometrial adenocarcinoma in culture and its development into an established line. Acta Obstet Gynaecol Jpn 19:47–58PubMedGoogle Scholar
  82. Kwong PD, Mascola JR, Nabel GJ (2012) The changing face of HIV vaccine research. J Int AIDS Soc 15:17407PubMedCentralPubMedGoogle Scholar
  83. Laga M, Piot P (2012) Prevention of sexual transmission of HIV: real results, science progressing, societies remaining behind. Aids 26:1223–1229PubMedGoogle Scholar
  84. Lagenaur LA, Sanders-Beer BE, Brichacek B, Pal R, Liu X, Liu Y, Yu R, Venzon D, Lee PP, Hamer DH (2011) Prevention of vaginal SHIV transmission in macaques by a live recombinant Lactobacillus. Mucosal Immunol 4:648–657PubMedCentralPubMedGoogle Scholar
  85. Lederman MM, Veazey RS, Offord R, Mosier DE, Dufour J, Mefford M, Piatak M Jr, Lifson JD, Salkowitz JR, Rodriguez B, Blauvelt A, Hartley O (2004) Prevention of vaginal SHIV transmission in rhesus macaques through inhibition of CCR5. Science 306:485–487PubMedGoogle Scholar
  86. Leibovitz A, Stinson JC, McCombs WB III, McCoy CE, Mazur KC, Mabry ND (1976) Classification of human colorectal adenocarcinoma cell lines. Cancer Res 36:4562–4569PubMedGoogle Scholar
  87. Li Q, Estes JD, Schlievert PM, Duan L, Brosnahan AJ, Southern PJ, Reilly CS, Peterson ML, Schultz-Darken N, Brunner KG, Nephew KR, Pambuccian S, Lifson JD, Carlis JV, Haase AT (2009) Glycerol monolaurate prevents mucosal SIV transmission. Nature 458:1034–1038PubMedCentralPubMedGoogle Scholar
  88. Lusso P, Cocchi F, Balotta C, Markham PD, Louie A, Farci P, Pal R, Gallo RC, Reitz MS Jr (1995) Growth of macrophage-tropic and primary human immunodeficiency virus type 1 (HIV-1) isolates in a unique CD4+ T-cell clone (PM1): failure to downregulate CD4 and to interfere with cell-line-tropic HIV-1. J Virol 69:3712–3720PubMedCentralPubMedGoogle Scholar
  89. Maeda K, Das D, Ogata-Aoki H, Nakata H, Miyakawa T, Tojo Y, Norman R, Takaoka Y, Ding J, Arnold GF, Arnold E, Mitsuya H (2006) Structural and molecular interactions of CCR5 inhibitors with CCR5. J Biol Chem 281:12688–12698PubMedGoogle Scholar
  90. Mahalingam A, Simmons AP, Ugaonkar SR, Watson KM, Dezzutti CS, Rohan LC, Buckheit RW Jr, Kiser PF (2011) Vaginal microbicide gel for delivery of IQP-0528, a pyrimidinedione analog with a dual mechanism of action against HIV-1. Antimicrob Agents Chemother 55:1650–1660PubMedCentralPubMedGoogle Scholar
  91. Malkovsky M, Newell A, Dalgleish A (1998) Inactivation of HIV by nonoxynol-9. Lancet 1:645Google Scholar
  92. Mayer K, Peipert J, Fleming T, Fullem A, Moench T, Cu-Uvin S, Bentley M, Chesney M, Rosenberg Z (2001) Safety and tolerability of BufferGel, a novel vaginal microbicide, in women in the United States. Clin Infect Dis 32:476–482PubMedGoogle Scholar
  93. McElrath MJ, Ballweber L, Terker A, Kreger A, Sakchalathorn P, Robinson B, Fialkow M, Lentz G, Hladik F (2010) Ex vivo comparison of microbicide efficacies for preventing HIV-1 genomic integration in intraepithelial vaginal cells. Antimicrob Agents Chemother 54:763–772PubMedCentralPubMedGoogle Scholar
  94. McGowan I, Gomez K, Bruder K, Febo I, Chen BA, Richardson BA, Husnik M, Livant E, Price C, Jacobson C (2011) Phase 1 randomized trial of the vaginal safety and acceptability of SPL7013 gel (VivaGel) in sexually active young women (MTN-004). Aids 25:1057–1064PubMedCentralPubMedGoogle Scholar
  95. McMichael AJ, Borrow P, Tomaras GD, Goonetilleke N, Haynes BF (2010) The immune response during acute HIV-1 infection: clues for vaccine development. Nat Rev Immunol 10:11–23PubMedCentralPubMedGoogle Scholar
  96. Mehellou Y, De Clercq E (2010) Twenty-six years of anti-HIV drug discovery: where do we stand and where do we go? J Med Chem 53:521–538PubMedGoogle Scholar
  97. Miller Jenkins LM, Ott DE, Hayashi R, Coren LV, Wang D, Xu Q, Schito ML, Inman JK, Appella DH, Appella E (2010) Small-molecule inactivation of HIV-1 NCp7 by repetitive intracellular acyl transfer. Nat Chem Biol 6:887–889PubMedGoogle Scholar
  98. Morris G, Chindrove S, Woodhall S, Wiggins R, Vcelar B, Lacey C (2010) A prospective randomized double blind placebo-controlled phase I pharmacokinetic and safety study of a vaginal microbicide gel containing three potent broadly neutralizing antibodies [2F5, 2G12, 4E10][MabGel]. Paper presented at Microbicides 2010, Pittsburgh Google Scholar
  99. MTN (2011) MTN statement on decision to discontinue use of tenofovir gel in VOICE, a major HIV prevention study in women.
  100. Neagu MR, Ziegler P, Pertel T, Strambio-De-Castillia C, Grutter C, Martinetti G, Mazzucchelli L, Grutter M, Manz MG, Luban J (2009) Potent inhibition of HIV-1 by TRIM5-cyclophilin fusion proteins engineered from human components. J Clin Invest 119:3035–3047PubMedCentralPubMedGoogle Scholar
  101. Nel A, Smythe S, Young K, Malcolm K, McCoy C, Rosenberg Z, Romano J (2009a) Safety and pharmacokinetics of dapivirine delivery from matrix and reservoir intravaginal rings to HIV-negative women. J Acquir Immune Defic Syndr 51:416–423PubMedGoogle Scholar
  102. Nel AM, Coplan P, van de Wijgert JH, Kapiga SH, von Mollendorf C, Geubbels E, Vyankandondera J, Rees HV, Masenga G, Kiwelu I, Moyes J, Smythe SC (2009b) Safety, tolerability, and systemic absorption of dapivirine vaginal microbicide gel in healthy, HIV-negative women. Aids 23:1531–1538PubMedGoogle Scholar
  103. NIAID (2011) Safety and effectiveness of tenofovir 1 % gel, tenofovir disproxil fumarate, and emtricitabine/tenofovir disoproxil fumarate tablets in preventing HIV in women.
  104. Nisole S, Saib A (2004) Early steps of retrovirus replicative cycle. Retrovirology 1:9PubMedCentralPubMedGoogle Scholar
  105. Nuttall J, Romano J, Douville K, Galbreath C, Nel A, Heyward W, Mitchnick M, Walker S, Rosenberg Z (2007) The future of HIV prevention: prospects for an effective anti-HIV microbicide. Infect Dis Clin North Am 21:219–239, xGoogle Scholar
  106. Nuttall JP, Thake DC, Lewis MG, Ferkany JW, Romano JW, Mitchnick MA (2008) Concentrations of dapivirine in the rhesus macaque and rabbit following once daily intravaginal administration of a gel formulation of [14C]dapivirine for 7 days. Antimicrob Agents Chemother 52:909–914PubMedCentralPubMedGoogle Scholar
  107. O’Connor T, Kinchington D, Kangro HO, Jeffries DJ (1995) The activity of candidate virucidal agents, low pH and genital secretions against HIV-1 in vitro. Int J STD AIDS 6:267–272PubMedGoogle Scholar
  108. O’Hara BM, Olson WC (2002) HIV entry inhibitors in clinical development. Curr Opin Pharmacol 2:523–528PubMedGoogle Scholar
  109. O’Keefe BR, Vojdani F, Buffa V, Shattock RJ, Montefiori DC, Bakke J, Mirsalis J, d’Andrea AL, Hume SD, Bratcher B, Saucedo CJ, McMahon JB, Pogue GP, Palmer KE (2009) 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 106:6099–6104PubMedCentralPubMedGoogle Scholar
  110. Parikh UM, Dobard C, Sharma S, Cong ME, Jia H, Martin A, Pau CP, Hanson DL, Guenthner P, Smith J, Kersh E, Garcia-Lerma JG, Novembre FJ, Otten R, Folks T, Heneine W (2009) Complete protection from repeated vaginal simian–human immunodeficiency virus exposures in macaques by a topical gel containing tenofovir alone or with emtricitabine. J Virol 83:10358–10365PubMedCentralPubMedGoogle Scholar
  111. Pastore C, Picchio GR, Galimi F, Fish R, Hartley O, Offord RE, Mosier DE (2003) Two mechanisms for human immunodeficiency virus type 1 inhibition by N-terminal modifications of RANTES. Antimicrob Agents Chemother 47:509–517PubMedCentralPubMedGoogle Scholar
  112. Pilcher CD, Tien HC, Eron JJ Jr, Vernazza PL, Leu SY, Stewart PW, Goh LE, Cohen MS (2004) Brief but efficient: acute HIV infection and the sexual transmission of HIV. J Infect Dis 189:1785–1792PubMedGoogle Scholar
  113. Polonis VR, Brown BK, Rosa Borges A, Zolla-Pazner S, Dimitrov DS, Zhang MY, Barnett SW, Ruprecht RM, Scarlatti G, Fenyo EM, Montefiori DC, McCutchan FE, Michael NL (2008) Recent advances in the characterization of HIV-1 neutralization assays for standardized evaluation of the antibody response to infection and vaccination. Virology 375:315–320PubMedGoogle Scholar
  114. Powderly WG (2010) Integrase inhibitors in the treatment of HIV-1 infection. J Antimicrob Chemother 65:2485–2488PubMedGoogle Scholar
  115. Ramjee G, Kamali A, McCormack S (2010) The last decade of microbicide clinical trials in Africa: from hypothesis to facts. AIDS 24:S40–S49PubMedGoogle Scholar
  116. Richardson-Harman N, Lackman-Smith C, Fletcher PS, Anton PA, Bremer JW, Dezzutti CS, Elliott J, Grivel JC, Guenthner P, Gupta P, Jones M, Lurain NS, Margolis LB, Mohan S, Ratner D, Reichelderfer P, Roberts P, Shattock RJ, Cummins JE Jr (2009) Multisite comparison of anti-human immunodeficiency virus microbicide activity in explant assays using a novel endpoint analysis. J Clin Microbiol 47:3530–3539PubMedCentralPubMedGoogle Scholar
  117. Roberts L, Liebenberg L, Barnabas S, Passmore JA (2012a) Vaginal microbicides to prevent human immunodeficiency virus infection in women: Perspectives on the female genital tract, sexual maturity and mucosal inflammation. Best Pract Res Clin Obstet Gynaecol 26:441–449PubMedGoogle Scholar
  118. Roberts L, Passmore JA, Mlisana K, Williamson C, Little F, Bebell LM, Walzl G, Abrahams MR, Woodman Z, Abdool Karim Q, Abdool Karim SS (2012b) Genital tract inflammation during early HIV-1 infection predicts higher plasma viral load set point in women. J Infect Dis 205:194–203PubMedCentralPubMedGoogle Scholar
  119. Romano J, Variano B, Coplan P, Van Roey J, Douville K, Rosenberg Z, Temmerman M, Verstraelen H, Van Bortel L, Weyers S, Mitchnick M (2009) Safety and availability of dapivirine (TMC120) delivered from an intra-vaginal ring. AIDS Res Hum Retroviruses 25:483–488PubMedGoogle Scholar
  120. Salazar-Gonzalez JF, Salazar MG, Keele BF, Learn GH, Giorgi EE, Li H, Decker JM, Wang S, Baalwa J, Kraus MH, Parrish NF, Shaw KS, Guffey MB, Bar KJ, Davis KL, Ochsenbauer-Jambor C, Kappes JC, Saag MS, Cohen MS, Mulenga J, Derdeyn CA, Allen S, Hunter E, Markowitz M, Hraber P, Perelson AS, Bhattacharya T, Haynes BF, Korber BT, Hahn BH, Shaw GM (2009) Genetic identity, biological phenotype, and evolutionary pathways of transmitted/founder viruses in acute and early HIV-1 infection. J Exp Med 206:1273–1289PubMedCentralPubMedGoogle Scholar
  121. Sexton A, Harman S, Shattock RJ, Ma K-C (2009) Design, expression, and characterization of a multivalent, combination HIV microbicide. FASEB J 23:3590–3600PubMedGoogle Scholar
  122. Shattock RJ, Moore JP (2003) Inhibiting sexual transmission of HIV-1 infection. Nat Rev Microbiol 1:25–34PubMedGoogle Scholar
  123. Shattock RJ, Rosenberg Z (2012) Microbicides: topical prevention against HIV. Cold Spring Harb Perspect Med 2:a007385PubMedCentralPubMedGoogle Scholar
  124. Shattock RJ, Warren M, McCormack S, Hankins CA (2011) AIDS. Turning the tide against HIV. Science 333:42–43Google Scholar
  125. Si Z, Madani N, Cox JM, Chruma JJ, Klein JC, Schon A, Phan N, Wang L, Biorn AC, Cocklin S, Chaiken I, Freire E, Smith AB 3rd, Sodroski JG (2004) Small-molecule inhibitors of HIV-1 entry block receptor-induced conformational changes in the viral envelope glycoproteins. Proc Natl Acad Sci U S A 101:5036–5041PubMedCentralPubMedGoogle Scholar
  126. Singer R, Derby N, Rodriguez A, Kizima L, Kenney J, Aravantinou M, Chudolij A, Gettie A, Blanchard J, Lifson JD, Piatak M Jr, Fernandez-Romero JA, Zydowsky TM, Robbiani M (2011) The nonnucleoside reverse transcriptase inhibitor MIV-150 in carrageenan gel prevents rectal transmission of simian/human immunodeficiency virus infection in macaques. J Virol 85:5504–5512PubMedCentralPubMedGoogle Scholar
  127. Slater TF, Sawyer B, Straeuli U (1963) Studies on succinate–tetrazolium reductase systems. III. Points of coupling of four different tetrazolium salts. Biochim Biophys Acta 77:383–393PubMedGoogle Scholar
  128. Stefanidou M, Herrera C, Armanasco N, Shattock RJ (2012) Saquinavir inhibits early events associated with establishment of HIV-1 infection: potential role for protease inhibitors in prevention. Antimicrob Agents Chemother 56:4381–4390PubMedCentralPubMedGoogle Scholar
  129. Stiegler G, Armbruster C, Vcelar B, Stoiber H, Kunert R, Michael NL, Jagodzinski LL, Ammann C, Jager W, Jacobson J, Vetter N, Katinger H (2002) Antiviral activity of the neutralizing antibodies 2F5 and 2G12 in asymptomatic HIV-1-infected humans: a phase I evaluation. Aids 16:2019–2025PubMedGoogle Scholar
  130. Stremlau M, Owens CM, Perron MJ, Kiessling M, Autissier P, Sodroski J (2004) The cytoplasmic body component TRIM5alpha restricts HIV-1 infection in Old World monkeys. Nature 427:848–853PubMedGoogle Scholar
  131. Sykes JA, Whitescarver J, Jernstrom P, Nolan JF, Byatt P (1970) Some properties of a new epithelial cell line of human origin. J Natl Cancer Inst 45:107–122PubMedGoogle Scholar
  132. Telwatte S, Moore K, Johnson A, Tyssen D, Sterjovski J, Aldunate M, Gorry PR, Ramsland PA, Lewis GR, Paull JR, Sonza S, Tachedjian G (2011) Virucidal activity of the dendrimer microbicide SPL7013 against HIV-1. Antiviral Res 90:195–199PubMedCentralPubMedGoogle Scholar
  133. Terrazas-Aranda K, Van Herrewege Y, Hazuda D, Lewi P, Costi R, Di Santo R, Cara A, Vanham G (2008) Human immunodeficiency virus type 1 (HIV-1) integration: a potential target for microbicides to prevent cell-free or cell-associated HIV-1 infection. Antimicrob Agents Chemother 52:2544–2554PubMedCentralPubMedGoogle Scholar
  134. Tozser J, Shulenin S, Kadas J, Boross P, Bagossi P, Copeland TD, Nair BC, Sarn-gadharan MG, Oroszlan S (2003) Human immunodeficiency virus type 1 capsid protein is a substrate of the retroviral proteinase while integrase is resistant toward proteolysis. Virology 310:16–23PubMedGoogle Scholar
  135. Trkola A, Ketas TJ, Nagashima KA, Zhao L, Cilliers T, Morris L, Moore JP, Maddon PJ, Olson WC (2001) Potent, broad-spectrum inhibition of human immunodeficiency virus type 1 by the CCR5 monoclonal antibody PRO 140. J Virol 75:579–588PubMedCentralPubMedGoogle Scholar
  136. Trkola A, Kuster H, Rusert P, Joos B, Fischer M, Leemann C, Manrique A, Huber M, Rehr M, Oxenius A, Weber R, Stiegler G, Vcelar B, Katinger H, Aceto L, Gunthard HF (2005) Delay of HIV-1 rebound after cessation of antiretroviral therapy through passive transfer of human neutralizing anti-bodies. Nat Med 11:615–622PubMedGoogle Scholar
  137. Trkola A, Pomales AB, Yuan H, Korber B, Maddon PJ, Allaway GP, Katinger H, Barbas CF 3rd, Burton DR, Ho DD et al (1995) Cross-clade neutralization of primary isolates of human immunodeficiency virus type 1 by human monoclonal antibodies and tetrameric CD4-IgG. J Virol 69:6609–6617PubMedCentralPubMedGoogle Scholar
  138. Tsai CC, Emau P, Jiang Y, Agy MB, Shattock RJ, Schmidt A, Morton WR, Gustafson KR, Boyd MR (2004) Cyanovirin-N inhibits AIDS virus infections in vaginal transmission models. AIDS Res Hum Retroviruses 20:11–18PubMedGoogle Scholar
  139. Tsai CC, Emau P, Jiang Y, Tian B, Morton WR, Gustafson KR, Boyd MR (2003) Cyanovirin-N gel as a topical microbicide prevents rectal transmission of SHIV89.6P in macaques. AIDS Res Hum Retroviruses 19:535–541PubMedGoogle Scholar
  140. Van Damme L, Ramjee G, Alary M, Vuylsteke B, Chandeying V, Rees H, Sirivongrangson P, Mukenge-Tshibaka L, Ettiègne-Traoré V, Uaheowitchai C, Karim SS, Mâsse B, Perriëns J, Laga M, Group C-S (2002) Effectiveness of COL-1492, a nonoxynol-9 vaginal gel, on HIV-1 transmission in female sex workers: a randomised controlled trial. Lancet 360:971–977Google Scholar
  141. van der Straten A, Van Damme L, Haberer JE, Bangsberg DR (2012) Unraveling the divergent results of pre-exposure prophylaxis trials for HIV prevention. Aids 26:F13–F19PubMedGoogle Scholar
  142. Van Herrewege Y, Michiels J, Waeytens A, De Boeck G, Salden E, Heyndrickx L, van den Mooter G, de Bethune MP, Andries K, Lewi P, Praet M, Vanham G (2007) A dual chamber model of female cervical mucosa for the study of HIV transmission and for the evaluation of candidate HIV microbicides. Antiviral Res 74:111–124PubMedGoogle Scholar
  143. Van Herrewege Y, Morellato L, Descours A, Aerts L, Michiels J, Heyndrickx L, Martin L, Vanham G (2008) CD4 mimetic miniproteins: potent anti-HIV compounds with promising activity as microbicides. J Antimicrob Chemother 61:818–826PubMedGoogle Scholar
  144. van’t Wout AB, Kootstra NA, Mulder-Kampinga GA, Albrecht-van Lent N, Scherpbier HJ, Veenstra J, Boer K, Coutinho RA, Miedema F, Schuitemaker H (1994) Macrophage-tropic variants initiate human immunodeficiency virus type 1 infection after sexual, parenteral, and vertical transmission. J Clin Invest 94:2060–2067Google Scholar
  145. Vazquez N, Schmeisser H, Dolan MA, Bekisz J, Zoon KC, Wahl SM (2011) Structural variants of IFNalpha preferentially promote antiviral functions. Blood 118:2567–2577PubMedCentralPubMedGoogle Scholar
  146. Veazey RS, Ketas TA, Klasse PJ, Davison DK, Singletary M, Green LC, Greenberg ML, Moore JP (2008) Tropism-independent protection of macaques against vaginal transmission of three SHIVs by the HIV-1 fusion inhibitor T-1249. Proc Natl Acad Sci U S A 105:10531–10536PubMedCentralPubMedGoogle Scholar
  147. Veazey RS, Ketas TJ, Dufour J, Moroney-Rasmussen T, Green LC, Klasse PJ, Moore JP (2010) Protection of rhesus macaques from vaginal infection by vaginally delivered maraviroc, an inhibitor of HIV-1 entry via the CCR5 co-receptor. J Infect Dis 202:739–744PubMedCentralPubMedGoogle Scholar
  148. Veazey RS, Klasse PJ, Schader SM, Hu Q, Ketas TJ, Lu M, Marx PA, Dufour J, Colonno RJ, Shattock RJ, Springer MS, Moore JP (2005) Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion. Nature 438:99–102PubMedGoogle Scholar
  149. Veazey RS, Ling B, Green LC, Ribka EP, Lifson JD, Piatak M Jr, Lederman MM, Mosier D, Offord R, Hartley O (2009) Topically applied recombinant chemokine analogues fully protect macaques from vaginal simian–human immunodeficiency virus challenge. J Infect Dis 199:1525–1527PubMedCentralPubMedGoogle Scholar
  150. Veazey RS, Shattock RJ, Klasse PJ, Moore JP (2012) Animal models for microbicide studies. Curr HIV Res 10:79–87PubMedCentralPubMedGoogle Scholar
  151. Veazey RS, Shattock RJ, Pope M, Kirijan JC, Jones J, Hu Q, Ketas T, Marx PA, Klasse PJ, Burton DR, Moore JP (2003) Prevention of virus transmission to macaque monkeys by a vaginally applied monoclonal antibody to HIV-1 gp120. Nat Med 9:343–346PubMedGoogle Scholar
  152. Venkatraj M, Arien KK, Heeres J, Dirie B, Joossens J, Van Goethem S, Van der Veken P, Michiels J, Vande Velde CM, Vanham G, Lewi PJ, Augustyns K (2011) Novel diarylpyridinones, diarylpyridazinones and diarylphthalazinones as potential HIV-1 nonnucleoside reverse transcriptase inhibitors (NNRTIs). Bioorg Med Chem 19:5924–5934PubMedGoogle Scholar
  153. Vermeire K, Brouwers J, Van Herrewege Y, Le Grand R, Vanham G, Augustijns P, Bell TW, Schols D (2008) CADA, a potential anti-HIV microbicide that specifically targets the cellular CD4 receptor. Curr HIV Res 6:246–256PubMedGoogle Scholar
  154. Veselinovic M, Preston Neff C, Mulder LR, Akkina R (2012) Topical gel formulation of broadly neutralizing anti-HIV-1 monoclonal antibody VRC01 confers protection against HIV-1 vaginal challenge in a humanized mouse model. Virology 432:505-510Google Scholar
  155. Walker LM, Huber M, Doores KJ, Falkowska E, Pejchal R, Julien JP, Wang SK, Ramos A, Chan-Hui PY, Moyle M, Mitcham JL, Hammond PW, Olsen OA, Phung P, Fling S, Wong CH, Phogat S, Wrin T, Simek MD, Koff WC, Wilson IA, Burton DR, Poignard P (2011) Broad neutralization coverage of HIV by multiple highly potent antibodies. Nature 477:466–470PubMedCentralPubMedGoogle Scholar
  156. Wallace GS, Cheng-Mayer C, Schito ML, Fletcher P, Miller Jenkins LM, Hayashi R, Neurath AR, Appella E, Shattock RJ (2009) Human immunodeficiency virus type 1 nucleocapsid inhibitors impede trans infection in cellular and explant models and protect nonhuman primates from infection. J Virol 83:9175–9182PubMedCentralPubMedGoogle Scholar
  157. Wang G, Watson KM, Peterkofsky A, Buckheit RW Jr (2010) Identification of novel human immunodeficiency virus type 1-inhibitory peptides based on the antimicrobial peptide database. Antimicrob Agents Chemother 54:1343–1346PubMedCentralPubMedGoogle Scholar
  158. Wei X, Decker JM, Liu H, Zhang Z, Arani RB, Kilby JM, Saag MS, Wu X, Shaw GM, Kappes JC (2002) Emergence of resistant human immunodeficiency virus type 1 in patients receiving fusion inhibitor (T-20) monotherapy. Antimicrob Agents Chemother 46:1896–1905PubMedCentralPubMedGoogle Scholar
  159. Wheeler LA, Trifonova R, Vrbanac V, Basar E, McKernan S, Xu Z, Seung E, Deruaz M, Dudek T, Einarsson JI, Yang L, Allen TM, Luster AD, Tager AM, Dykxhoorn DM, Lieberman J (2011) Inhibition of HIV transmission in human cervicovaginal explants and humanized mice using CD4 aptamer–siRNA chimeras. J Clin Invest 121:2401–2412PubMedCentralPubMedGoogle Scholar
  160. Wiznia AA, Crane M, Lambert G, Sansary J, Harris A, Solomon L (1996) Zidovudine use to reduce perinatal HIV type 1 transmission in an urban medical center. JAMA 275:1504–1506PubMedGoogle Scholar
  161. Zhao B, Mankowski MK, Snyder BA, Ptak RG, Liwang PJ (2011) Highly potent chimeric inhibitors targeting two steps of HIV cell entry. J Biol Chem 286:28370–28381PubMedCentralPubMedGoogle Scholar
  162. Zhou T, Georgiev I, Wu X, Yang ZY, Dai K, Finzi A, Kwon YD, Scheid JF, Shi W, Xu L, Yang Y, Zhu J, Nussenzweig MC, Sodroski J, Shapiro L, Nabel GJ, Mascola JR, Kwong PD (2010) Structural basis for broad and potent neutralization of HIV-1 by antibody VRC01. Science 329:811–817PubMedCentralPubMedGoogle Scholar
  163. Zhu T, Mo H, Wang N, Nam DS, Cao Y, Koup RA, Ho DD (1993) Genotypic and phenotypic characterization of HIV-1 patients with primary infection. Science 261:1179–1181PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  1. 1.Section of Infectious Diseases, Faculty of MedicineWright-Fleming Institute, St. Mary’s Campus, Imperial CollegeLondonUK

Personalised recommendations