Open AccessMutations of Gln64 in the HIV-1 gp41 N-Terminal Heptad Repeat Render Viruses Resistant to Peptide HIV Fusion Inhibitors Targeting the gp41 Pocket
Author(s) -
Xiang Yu,
Lu Lu,
Lifeng Cai,
Pei Tong,
Suiyi Tan,
Peng Zou,
Fanxia Meng,
Yinghua Chen,
Shibo Jiang
Publication year - 2012
Publication title -
journal of virology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.617
H-Index - 292
eISSN - 1070-6321
pISSN - 0022-538X
DOI - 10.1128/jvi.05066-11
Subject(s) - gp41 , heptad repeat , enfuvirtide , biology , human immunodeficiency virus (hiv) , peptide , lipid bilayer fusion , binding site , virology , plasma protein binding , biochemistry , peptide sequence , genetics , virus , gene , antigen , epitope
To prove that the peptidic HIV-1 fusion inhibitors containing the pocket-binding domain (PBD) mainly target the hydrophobic pocket in the gp41 N-terminal heptad repeat (NHR), we constructed pseudoviruses by replacement of Q64 in the gp41 pocket region with Ala (Q64A) or Leu (Q64L). These viruses were highly resistant to C34 and CP32M containing the PBD, while they were susceptible to T20 (enfuvirtide) lacking the PBD but containing the GIV-motif-binding domain (GBD) and lipid-binding domain (LBD). They were also sensitive to C52L, which contains the PBD, GBD, and LBD. Those mutations may disrupt the hydrophilic interaction between Q64 in the NHR and N113 in the peptides containing the PBD. This report provides insights into the mechanisms of drug resistance, with implications for the design of novel HIV fusion and entry inhibitors.