Characterization of HIV-1 resistance to a fusion inhibitor, N36, derived from the gp41 amino-terminal heptad repeat

Kazuki Izumi, Shota Nakamura, Hiroaki Nakano, Kazuya Shimura, Yasuko Sakagami, Shinya Oishi, Susumu Uchiyama, Tadayasu Ohkubo, Yuji Kobayashi, Nobutaka Fujii, Masao Matsuoka, Eiichi N. Kodama

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16 Citations (Scopus)


A transmembrane glycoprotein of HIV-1, gp41, plays a central role in membrane fusion of HIV-1 and host cells. Peptides derived from the amino- and carboxyl-terminal heptad repeat (N-HR and C-HR, respectively) of gp41 inhibit this fusion. The mechanism of resistance to enfuvirtide, a C-HR-derived peptide, is well defined; however the mechanism of resistance to N-HR-derived peptides remains unclear. We characterized an HIV-1 isolate resistant to the N-HR-derived peptide, N36. This HIV-1 acquired a total of four amino acid substitutions, D36G, N126K and E137Q in gp41, and P183Q in gp120. Among these substitutions, N126K and/or E137Q conferred resistance to not only N36, but also C34, which is the corresponding C-HR-derived peptide fusion inhibitor. We performed crystallographic and biochemical analysis of the 6-helix bundle formed by synthetic gp41-derived peptides containing the N126K/E137Q substitutions. The structure of the 6-helix bundle with N126K/E137Q was identical to that in wild-type HIV-1 except for the presence of a new hydrogen bond. Denaturing experiments revealed that the stability of the 6-helix bundle of N126K/E137Q is greater than in the wild-type. These results suggest that the stabilizing effect of N126K/E137Q provides resistance to N36 and C34.

Original languageEnglish
Pages (from-to)179-186
Number of pages8
JournalAntiviral Research
Issue number2
Publication statusPublished - 2010 Aug


  • Amino-terminus
  • Fusion
  • Gp41
  • HIV-1
  • Resistance


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