Mechanism of resistance to S138A substituted enfuvirtide and its application to peptide design

Kazuki Izumi, Kumi Kawaji, Fusasko Miyamoto, Kazuki Shimane, Kazuya Shimura, Yasuko Sakagami, Toshio Hattori, Kentaro Watanabe, Shinya Oishi, Nobutaka Fujii, Masao Matsuoka, Mitsuo Kaku, Stefan G. Sarafianos, Eiichi N. Kodama

Research output: Contribution to journalArticlepeer-review

6 Citations (Scopus)

Abstract

T-20 (enfuvirtide) resistance is caused by the N43D primary resistance mutation at its presumed binding site at the N-terminal heptad repeat (N-HR) of gp41, accompanied by the S138A secondary mutation at the C-terminal HR of gp41 (C-HR). We have discovered that modifying T-20 to include S138A (T-20 S138A) allows it to efficiently block wild-type and T20-resistant viruses, by a mechanism that involves improved binding of T-20S138A to the N-HR that contains the N43D primary mutation. To determine how HIV-1 in turn escapes T-20S138A we used a dose escalation method to select T-20S138A-resistant HIV-1 starting with either wild-type (HIV-1 WT) or T-20-resistant (HIV-1N43D/S138A) virus. We found that when starting with WT background, I37N and L44M emerged in the N-HR of gp41, and N126K in the C-HR. However, when starting with HIV-1 N43D/S138A, L33S and I69L emerged in N-HR, and E137K in C-HR. T-20S138A-resistant recombinant HIV-1 showed cross-resistance to other T-20 derivatives, but not to C34 derivatives, suggesting that T-20 S138A suppressed HIV-1 replication by a similar mechanism to T-20. Furthermore, E137K enhanced viral replication kinetics and restored binding affinity with N-HR containing N43D, indicating that it acts as a secondary, compensatory mutation. We therefore introduced E137K into T-20S138A (T-20E137K/S138A) and revealed that T-20E137K/S138A moderately suppressed replication of T-20S138A-resistant HIV-1. T-20E137K/S138A retained activity to HIV-1 without L33S, which seems to be a key mutation for T-20 derivatives. Our data demonstrate that secondary mutations can be consistently used for the design of peptide inhibitors that block replication of HIV resistant to fusion inhibitors.

Original languageEnglish
Pages (from-to)908-915
Number of pages8
JournalInternational Journal of Biochemistry and Cell Biology
Volume45
Issue number4
DOIs
Publication statusPublished - 2013 Apr 1

Keywords

  • Fusion inhibitor
  • HIV-1
  • Mutation
  • Resistance
  • T-20
  • gp41

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology

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