Escape pathways of HIV-1 viruses that are resistance to peptides corresponding to the N-heptad repeat region (HR1) of gp41

Tuesday, October 09, 2012 — Poster Session I
1:00 p.m. – 3:00 p.m	Natcher Conference Center, Building 45	FDA/CBER	VIROL-3

Authors

• C.J. De Feo
• W. Wang
• M. Zhuang
• R. Vassell
• C.D. Weiss

Abstract

Peptides corresponding to the N- and C-terminal heptad-repeat regions (HR1 and HR2, respectively) in the HIV Envelope (Env) transmembrane glycoprotein gp41 can block infection in a dominant-negative manner by interfering with a critical folding step that is required to drive fusion between viral and host cell membranes. Of these two classes of peptide fusion inhibitors, less is known about the inhibitory mechanisms of HR1 peptides. To better understand the mechanisms of Env entry and inhibition by HR1 peptides, we generated HIV-1 cultures that are resistant to either of the following peptides: 1) N36 or 2) N44, corresponding to 36 or 44 residues from HR1, respectively, or 3) N36 with a coiled-coil trimerization domain fused to its N-terminus (IZN36) that stabilizes the trimer and increases inhibitor potency. Two genetic pathways emerged that were defined by acquisition of a specific mutation in either HR1 or HR2. Additional evaluation of the resistant Envs using pseudovirus and cell-cell fusion assays provides new insight into the role of these mutations in viral entry, env stability and resistance to entry inhibitors. Our findings inform inhibitor design and identify regions of plasticity in the highly conserved gp41 that modulate virus entry and sensitivity to HR1 peptides.

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