HIV-1 resistance to the gp41-dependent fusion inhibitor C-34.
The gp41 subunit of HIV-1 has been recently recognized as a target for antiviral therapy. C-34 is a peptide that mimics the heptad repeat 2 in the ectodomain of gp41. Here, we describe two HIV-1 strains selected after 5 and 17 passages in culture with increasing concentrations of C-34 (breakthrough concentration of 10 microg/ml). The HXB2-derived strain was more than 1000-fold resistant and contained a V38E mutation in the gp41 coding DNA sequence. The NL4-3-derived strain was more than 500-fold resistant and contained a L33S mutation in gp41. No cross-resistance to the RT inhibitor AZT, the HIV binding inhibitor dextran sulfate (DS), or the chemokine receptor antagonist ALX-40-4C was detected. These data indicate that HIV-1 can overcome C-34 inhibition through mutations at residues not involved in the formation of the hydrophobic cavity of gp41.
Armand-Ugón
Mercedes
M
Hospital Germans Trias i Pujol, Universitat Autónoma de Bercelona, 08916 Badalona, Spain.
Gutiérrez
Arantxa
A
Clotet
Bonaventura
B
Esté
José A
JA
D000595:Amino Acid Sequence; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral / Q000235:genetics; D015700:HIV Envelope Protein gp41 / Q000235:genetics / Q000494:pharmacology* / Q000502:physiology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000472:pathogenicity / Q000502:physiology*; D006801:Humans; D066298:In Vitro Techniques; D008561:Membrane Fusion / Q000187:drug effects; D008969:Molecular Sequence Data; D009154:Mutation; D010446:Peptide Fragments / Q000494:pharmacology*
D019380:Anti-HIV Agents; D015700:HIV Envelope Protein gp41; D010446:Peptide Fragments; C407149:peptide C34