Protection of macaques from vaginal SHIV challenge by vaginally delivered inhibitors of virus-cell fusion

Nature. 2005 Nov 3;438(7064):99-102. doi: 10.1038/nature04055. Epub 2005 Oct 30.

Abstract

Human immunodeficiency virus type 1 (HIV-1) continues to spread, principally by heterosexual sex, but no vaccine is available. Hence, alternative prevention methods are needed to supplement educational and behavioural-modification programmes. One such approach is a vaginal microbicide: the application of inhibitory compounds before intercourse. Here, we have evaluated the microbicide concept using the rhesus macaque 'high dose' vaginal transmission model with a CCR5-receptor-using simian-human immunodeficiency virus (SHIV-162P3) and three compounds that inhibit different stages of the virus-cell attachment and entry process. These compounds are BMS-378806, a small molecule that binds the viral gp120 glycoprotein and prevents its attachment to the CD4 and CCR5 receptors, CMPD167, a small molecule that binds to CCR5 to inhibit gp120 association, and C52L, a bacterially expressed peptide inhibitor of gp41-mediated fusion. In vitro, all three compounds inhibit infection of T cells and cervical tissue explants, and C52L acts synergistically with CMPD167 or BMS-378806 to inhibit infection of cell lines. In vivo, significant protection was achieved using each compound alone and in combinations. CMPD167 and BMS-378806 were protective even when applied 6 h before challenge.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Administration, Intravaginal
  • Animals
  • Anti-HIV Agents / administration & dosage
  • Anti-HIV Agents / pharmacology*
  • CCR5 Receptor Antagonists
  • CD4 Antigens / metabolism
  • Cell Fusion
  • Drug Therapy, Combination
  • Female
  • HIV / drug effects*
  • HIV / metabolism
  • HIV Envelope Protein gp120 / metabolism
  • HIV Infections / prevention & control*
  • HIV Infections / transmission
  • HIV Infections / virology
  • Macaca mulatta / virology*
  • Membrane Fusion / drug effects*
  • Piperazines / administration & dosage
  • Piperazines / pharmacology
  • Pyrazoles / administration & dosage
  • Pyrazoles / pharmacology
  • Receptors, CCR5 / metabolism
  • Receptors, Virus / antagonists & inhibitors
  • Receptors, Virus / metabolism
  • Simian Acquired Immunodeficiency Syndrome / prevention & control*
  • Simian Acquired Immunodeficiency Syndrome / transmission
  • Simian Acquired Immunodeficiency Syndrome / virology
  • Simian Immunodeficiency Virus / drug effects
  • Simian Immunodeficiency Virus / metabolism
  • Time Factors
  • Vagina / drug effects
  • Vagina / virology*
  • Valine / administration & dosage
  • Valine / analogs & derivatives
  • Valine / pharmacology

Substances

  • Anti-HIV Agents
  • BMS-378806
  • CCR5 Receptor Antagonists
  • CD4 Antigens
  • HIV Envelope Protein gp120
  • N-(3-(3-fluorophenyl)-4-((4-(3-benzyl-1-ethylpyrazol-5-yl)piperidin-1-yl)methyl)cyclopentyl)-N-methylvaline
  • Piperazines
  • Pyrazoles
  • Receptors, CCR5
  • Receptors, Virus
  • Valine