Tropism-independent protection of macaques against vaginal transmission of three SHIVs by the HIV-1 fusion inhibitor T-1249 Academic Article uri icon

Overview

MeSH Major

  • HIV Fusion Inhibitors
  • HIV Infections
  • Simian Immunodeficiency Virus
  • Vagina

abstract

  • We have assessed the potential of the fusion inhibitory peptide T-1249 for development as a vaginal microbicide to prevent HIV-1 sexual transmission. When formulated as a simple gel, T-1249 provided dose-dependent protection to macaques against high-dose challenge with three different SHIVs that used either CCR5 or CXCR4 for infection (the R5 virus SHIV-162P3, the X4 virus SHIV-KU1 and the R5X4 virus SHIV-89.6P), and it also protected against SIVmac251 (R5). Protection of half of the test animals was estimated by interpolation to occur at T-1249 concentrations of approximately 40-130 muM, whereas complete protection was observed at 0.1-2 mM. In vitro, T-1249 had substantial breadth of activity against HIV-1 strains from multiple genetic subtypes and in a coreceptor-independent manner. Thus, at 1 muM in a peripheral blood mononuclear cell-based replication assay, T-1249 inhibited all 29 R5 viruses, all 12 X4 viruses and all 7 R5X4 viruses in the test panel, irrespective of their genetic subtype. Combining lower concentrations of T-1249 with other entry inhibitors (CMPD-167, BMS-C, or AMD3465) increased the proportion of test viruses that could be blocked. In the PhenoSense assay, T-1249 was active against 636 different HIV-1 Env-pseudotyped viruses of varying tropism and derived from clinical samples, with IC(50) values typically clustered in a 10-fold range approximately 10 nM. Overall, these results support the concept of using T-1249 as a component of an entry inhibitor-based combination microbicide to prevent the sexual transmission of diverse HIV-1 variants.

publication date

  • July 29, 2008

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2492474

Digital Object Identifier (DOI)

  • 10.1073/pnas.0802666105

PubMed ID

  • 18647836

Additional Document Info

start page

  • 10531

end page

  • 6

volume

  • 105

number

  • 30