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ST103 HIV-1 variants with mutations in the gp41 pocket region are resistant to HIV fusion inhibitors with pocket-binding domain, but sensitive to T20

Lua Lu; Tong, Pei; Yub, Xiaowen; Panc, Chungen; Zou, Peng; Chen, Ying-hua; Jiang, Shibo
JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2013
doi: 10.1097/01.qai.0000429264.98091.c5
Abstracts: PDF Only

Enfuvirtide (T20), the first FDA-approved peptide HIV fusion/entry inhibitor derived from the HIV-1 gp41 C-terminal heptad-repeat (CHR) domain, is believed to share a target with other CHR-peptides with pocket-binding domain (PBD), e.g., C34, T1144 and CP32M, by interacting with the gp41 N-terminal heptad-repeat (NHR) to form six-helix bundle (6-HB) core. However, our previous studies showed that T20 mainly interacts with the N-terminal region of the NHR (N-NHR) and lipid membranes, while other CHR peptides mainly binds to the NHR C-terminal pocket region. But so far, no one has shown that these peptides can induce drug-resistance mutation in the gp41 pocket region. In this study, we constructed pseudoviruses with substitution of Q64 or A67 in the gp41 pocket region with other residues and found that these mutations rendered the viruses highly resistant to the CHR-peptides with PBD, but sensitive to T20 which lacks PBD. However, the viruses with mutations resistant to T20 are highly sensitive to these mutated CHR-peptides. The stability of 6-HB formed by C34 and N36 with Q64 or A67 mutations was significantly lower than that formed by C34 and N36 with wild-type sequence. These results suggest that these CHR-peptides with PBD and T20 without PBD inhibit HIV-1 fusion by interacting with different target sites and the combinatorial use of these peptides and T20 is expected to be effective against HIV-1 variants resistant to T20 and other CHR-peptides.

© 2013 Lippincott Williams & Wilkins, Inc.