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

► T-20S138A, a resistance mutation introduced peptide, blocks T20-resistant HIV-1. ► To determine how HIV-1 escapes, we induced T-20S138A-resistant HIV-1 in vitro. ► We found that a unique mutation E137K in resistant HIV-1. ► E137K introduced T-20S138A suppressed replication of T-20S138A-resistant HIV-1. ► Mutations can be consistently useful for the design of peptide inhibitors.