Mutations of Gln64 in the HIV-1 gp41 N-terminal heptad repeat render viruses resistant to peptide HIV fusion inhibitors targeting the gp41 pocket.
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.
School of Life Sciences, Tsinghua University, Key Laboratory for Protein Sciences of MOE, Beijing 100084, China.
Xiaowen
X
Yu
Lu
L
Lu
Lifeng
L
Cai
Pei
P
Tong
Suiyi
S
Tan
Peng
P
Zou
Fanxia
F
Meng
Ying-Hua
YH
Chen
Shibo
S
Jiang
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D002460:Cell Line; D024882:Drug Resistance, Viral; D015700:HIV Envelope Protein gp41 / Q000737:chemistry* / Q000235:genetics* / Q000378:metabolism; D023581:HIV Fusion Inhibitors / Q000494:pharmacology*; D015658:HIV Infections / Q000821:virology*; D015497:HIV-1 / Q000737:chemistry / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D020079:Terminal Repeat Sequences / Q000187:drug effects
D015700:HIV Envelope Protein gp41; D023581:HIV Fusion Inhibitors; C514787:gp41 protein, Human immunodeficiency virus 1