Compensatory mutations rescue the virus replicative capacity of VIRIP-resistant HIV-1.
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.
IrsiCaixa, Hospital Universitari Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Spain.
Emmanuel
E
González-Ortega
Ester
E
Ballana
Roger
R
Badia
Bonaventura
B
Clotet
José A
JA
Esté
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics; D004357:Drug Synergism; D000077560:Enfuvirtide; D015700:HIV Envelope Protein gp41 / Q000494:pharmacology; D023581:HIV Fusion Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics*; D054298:Human Immunodeficiency Virus Proteins / Q000235:genetics; D006801:Humans; D008826:Microbial Sensitivity Tests; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects; D000515:alpha 1-Antitrypsin / Q000494:pharmacology*
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; D054298:Human Immunodeficiency Virus Proteins; D010446:Peptide Fragments; C561794:VIR-353; C519920:VIRIP peptide, human; D000515:alpha 1-Antitrypsin; D000077560:Enfuvirtide