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Expert Opinion on Investigational Drugs Volume 11, 2002 - Issue 8
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Miscellaneous

Considerations and development of topical microbicides to inhibit the sexual transmission of HIV

Jim A Turpin TherImmune Research Corporation, Infectious Disease and Immunology Department, 18761 North Frederick Avenue, Suite A, Gaithersburg, MD 20879, USA, Tel: +1 240 364 6075; Fax: +1 240 631 1317;, E-mail: [email protected]
Pages 1077-1097 | Published online: 24 Feb 2005

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  • ••Produced by the International WorkingGroup On Topical Microbicides. An updated policy document that outlines the considerations and design of clinical trials for candidate HIV topical microbicides.
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  • ••Cervical explant model of HIV transmissionfor assessment of topical microbicides. This model has been used to show the effectiveness of a number of topical microbicide formulations and predicted that N-9 would be highly cytotoxic.
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  • ••Cervical explant model using a Transwell system, which allows measurement of the passage of the virus through the explant epithelium without exposure to submucosal cells. Experiments in this paper show that both cell-associated and cell-free HIV can penetrate the epithelial layer and infect T cells and monocytes in the subepithelial mucosa.
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  • ••First of two papers (reference 44) detailingthe discovery and role of the ICAM-3/DC-SIGN lectin-like ligand on dendritic cells and its potential role in HIV transmission.
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  • ••Important paper suggesting that infectedmonocytes from seminal fluid can use integrin molecules to transmigrate out of the vaginal lumen.
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  • ••First report describing the Hu-SCID modelfor vaginal transmission.
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  • ••Paper describing the original ME180transcytosis assay.
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  • ••Part of a series of papers which describe arapid establishment of infection and dissemination to quiescent T cells by dendritic cells in the rhesus macaque.
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  • FROM THE CENTERS OF DISEASE CONTROL AND PREVENTION: CDC statement on study results of product containing nonoxyno1-9. JAMA (2000) 284:1376.
  • ••Statement by the CDC outlining theirdecision to recommend that N-9 no longer be considered safe for topical microbicide usage. This decision represents a set back as well as a land mark in topical microbicide development.
  • VAN DAMME L, NIRUTHISARD S, ATISOOK R et al.: Safety evaluation of nonoxyno1-9 gel in women at low risk of HIV infection. AIDS (1998) 12:433–437.
  • RICHARDSON BA, LAVREYS L, MARTIN HL Jr et al.: Evaluation of a low-dose nonoxyno1-9 gel for the prevention of sexually transmitted diseases: a randomized clinical trial. Sex. Transm. Dis. (2001) 28:394–400.
  • VAN DAMME L, CHANDEYING V, RAMJEE G et al.: Safety of multiple daily applications of COL-1492, a nonoxyno1-9 vaginal gel, among female sex workers. COL-1492 Phase II Study Group. AIDS (2000) 14:85–88.
  • MAUCK CK, BAKER JM, BARR SP, JOHANSON WM, ARCHER DF: A Phase I comparative study of three contraceptive vaginal films containing nonoxyno1-9. Postcoital testing and colposcopy. Contraception (1997) 56:97–102.
  • MARTIN HL JR, STEVENS CE, RICHARDSON BA et al.: Safety of a nonoxyno1-9 vaginal gel in Kenyan prostitutes. A randomized clinical trial. Sex. Transm. Dis. (1997) 24:279–283.
  • RUSTOMJEE R, ABDOOL KARIM Q, ABDOOL KARIM SS, LAGA M, STEIN Z: Phase I trial of nonoxyno1-9 film among sex workers in South Africa. AIDS (1999) 13:1511–1515.
  • RICHARDSON BA, MARTIN HL JR, STEVENS CE et al.: Use of nonoxyno1-9 and changes in vaginal lactobacilli. J. Infect. Dis. (1998) 178:441–445.
  • GAGNE N, CORMIER H, OMAR RF et al.: Protective effect of a thermoreversible gel against the toxicity of nonoxyno1-9. Sex. Transm. Dis. (1999) 26:177–183.
  • PHILLIPS DM, TAYLOR CL, ZACHAROPOULOS VR, MAGUIRE RA: Nonoxyno1-9 causes rapid exfoliation of sheets of rectal epithelium. Contraception (2000) 62:149–154.
  • ••Study demonstrating immediate exfoliationof rectal epithelium that is clinically undetectable after 10 h. No intermediate time points were assessed, but other performed trials cited with no effect of N-9 with shorter time frames, suggesting a fast healing/replacement process.
  • FICHOROVA RN, TUCKER LD, ANDERSON DJ: The molecular basis of nonoxyno1-9-induced vaginal inflammation and its possible relevance to human immunodeficiency virus Type 1 transmission. J. Infect. Dis. (2001) 184:418–428.
  • ••One of many papers from this laboratoryhighlighting the importance of the vaginal cytokine and chemokine response as a more sensitive measurement of cervicovaginal epithelial cell cytotoxicity.
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  • FICHOROVA RN, ANDERSON DJ: Differential expression of immunobiological mediators by immortalized human cervical and vaginal epithelial cells. Biol. Reprod. (1999) 60:508–514.
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  • ANDERSON DJ, POLITCH JA, TUCKER LD et al.: Quantitation of mediators of inflammation and immunity in genital tract secretions and their relevance to HIV Type 1 transmission. AIDS Res. Hum. Removiruses. (1998) Suppl. 1:S43–S49.
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  • TEVI-BENISSAN C, BELEC L, LEVY M et al.: hi vivo semen-associated pH neutralization of cervicovaginal secretions. Clin. Diagn. Lab. Immunol. (1997) 4:367–374.
  • ONGRADI J, CECCHERINI-NELLI L, PISTELLO M, SPECTERS, BENDINELLI M: Acid sensitivity of cell-free and cell-associated HIV-1: clinical implications. AIDS Res. Hum. Removiruses. (1990) 6:1433–1436.
  • BOSKEY E, JANSEN A, MERSKI M, WHALEY K, MOENCH T, CONE R: BufferGel favors in vitro growth of lactobacilli while inhibiting BV-associated organisms. Microbicides 2000Washington, DC, USA March 13–16 (2000). Abstract 6
  • BARONS, POAST J, LEE M, CLOYD M, NGUYEN D: Anti-HIV components of OTC vaginal preparations. Antiviral Res. (2001) 50:A62. Abstract 81.
  • CLARKE JG, PEIPERT JF, HILLIER SL et al.: Microflora changes with the use of a vaginal microbicide. S. Transm. Dis. (2002) 29:288–293.
  • SALIB NN, EL-GAMAL SA: Application of some polymers in the physiocochemical design of tablet formulation. Pliarmazie (1976) 31:718–721.
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  • BARONS, POAST J, NGUYEN D, CLOYD MW: Practical prevention of vaginal and rectal transmission of HIV by adapting the oral defense: use of commercial lubricants. AIDS Res. Hum. Retrovi_ruses (2001) 17:997–1002.
  • BARONS, POAST J, LEE M, CLOYD M NGUYEN D: Anti-HIV Components of OTC vaginal preparations. Antiviral Res. (2001) 50: A62, Abstract 81.
  • CATALONE BJ, MILLERS SJ, KREBS FC, MAMAMUD D, WIGDAHL B: Development of a cell line with altered sensitivity to the vaginal microbicide C31G: Investigating a Surfactant's mechanism of action. Antiviral Res. (2001) 50:A62, Abstract 80.
  • ••Interesting observation that cells can phenotypically adapt to the C31G surfactant.
  • KREBS FC, MILLER SR, MALAMUD D, HOWETT MK, WIGDAHL B: Inactivation of human immunodeficiency virus Type 1 by nonoxyno1-9, C31G, or an alkyl sulfate, sodium dodecyl sulfate. Antiviral Res. (1999) 43:157–173.
  • ••Report demonstrating the virucidal effectsof C31G on cell-free HIV-1. The virucidal effect is shown to be equivalent to other virucides tested.
  • THOMPSON KA, MALAMUD D, STOREY BT: Assessment of the anti-microbial agent C31G as a spermicide: comparison with nonoxyno1-9. Contraception (1996) 53:313–318.
  • BABA M, PAUWELS R, BALZARINI J, ARNOUT J, DESMYTER J, DE CLERCQ E: Mechanism of inhibitory effect of dextran sulfate and heparin on replication of human immunodeficiency virus in vitro. Proc. Nati Acad. Sci. USA. (1988) 85:6132–6136.
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  • DOMS RW, TRONO D: The plasma membrane as a combat zone in the HIV battlefield. Genes Dev. (2000) 14:2677–2688.
  • ••Excellent review outlining the interaction ofHIV with the cell, CD4 and chemokine coreceptors.
  • DOMS RW: Beyond receptor expression: the influence of receptor conformation, density, and affinity in HIV-1 infection. Virology (2000) 276:229–237.
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  • SHATTOCK RJ, DOMS RW: AIDS models microbicides could learn from vaccines. Nat. Med. (2002) 8:425.
  • LEWIS MG, WAGNER W, YALLEY-OGUNRO J, GREENHOUSE J, PROFY AT: Efficacy of PRO 2000 gel in a macaque model for vaginal HIV transmission. 8th Conference on Retro viruses and Opportunistic Infections (2001) Abstract 721.
  • NEURATH A, STRICK N, JIANG S, LI YY, DEBNATH A: Anti-HIV-1 activity of cellulose acetate phthalate: Synergy with soluble CD4 and induction of 'dead-end' gp41 six-helix bundles. BMC Infect Dis. (2002) 30, 2(1):6.
  • MELIKYAN GB, MARKOSYAN RM, HEMMATI H, DELMEDICO MK, LAMBERT DM, COHEN FS: Evidence that the transition of HIV-1 gp41 into a six-helix bundle, not the bundle configuration, induces membrane fusion. Cell Biol. (2000) 151:413–423.
  • ••Mechanism of action study for CAP.Identifies a unique mechanism of action much like that of the clinically approved entry inhibitor T-20.
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Websites

  • http://www.unaids.org/
  • ••UNAIDS web site: contains important upto date information on the AIDS pandemic.
  • Microbicide Research and Development Report January 2002, Alliance For Microbicide Development http:// www.microbicide.org/ microsesearch.progress.report.jan02.pdf
  • ••Highly informative website for currentstatus of topical microbicide development.

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