Journal
ANTIVIRAL RESEARCH
Volume 92, Issue 3, Pages 479-483Publisher
ELSEVIER
DOI: 10.1016/j.antiviral.2011.10.010
Keywords
HIV-1; Fitness; gp41; Fusion; Resistance
Categories
Funding
- EU [LSHP-CT-2004-503487]
- Spanish Ministerio de Ciencia e Innovacion [BFU2009-06958, SAF2007-63622-02]
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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. (C) 2011 Elsevier B.V. All rights reserved.
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