Compensatory mutations rescue the virus replicative capacity of VIRIP-resistant HIV-1

Emmanuel González-Ortega, Ester Ballana, Roger Badia, Bonaventura Clotet, José A. Esté

Research output: Contribution to journalArticleResearchpeer-review

24 Citations (Scopus)

Abstract

VIRIP has been identified as a highly specific natural inhibitor of HIV-1 that blocks HIV-1 gp41-dependent fusion by interacting with the gp41 fusion peptide. Two analogues of VIRIP (VIR-353 and VIR-576) with a few amino acid changes increase its antiretroviral potency by two orders of magnitude in cell culture. VIR-576 has been shown effective in a phase I/II clinical trial. Resistance to VIRIP and its analogue VIR-353 were generated after long-term passage in cell culture suggesting a high genetic barrier to resistance. Mutations conferring resistance to VIRIP and VIR-353 significantly reduced virus fitness. However, accumulation of additional mutations rescued the replication capacity of the virus while retaining resistance to VIR-353 and full sensitivity to T20. Combinations of VIR-353 and T20 had an additive effect on the inhibition of wild type HIV-1 replication, but only a single agent was active when combinations were tested against T20-resistant HIV-1, suggesting that both gp41 peptides do not interfere with each other in their binding to gp41. Our results provide additional support to the development of a new class of antiretroviral agents targeting gp41-dependent fusion. © 2011 Elsevier B.V.
Original languageEnglish
Pages (from-to)479-483
JournalAntiviral Research
Volume92
Issue number3
DOIs
Publication statusPublished - 1 Dec 2011

Keywords

  • Fitness
  • Fusion
  • gp41
  • HIV-1
  • Resistance

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