Peptides trap the human immunodeficiency virus type 1 envelope glycoprotein fusion intermediate at two sites.
Human immunodeficiency virus type 1 (HIV-1) entry into target cells requires folding of two heptad-repeat regions (N-HR and C-HR) of gp41 into a trimer of N-HR and C-HR hairpins, which brings viral and target cell membranes together to facilitate membrane fusion. Peptides corresponding to the N-HR and C-HR of gp41 are potent inhibitors of HIV infection. Here we report new findings on the mechanism of inhibition of a N-HR peptide and compare these data with inhibition by a C-HR peptide. Using intact envelope glycoprotein (Env) under fusogenic conditions, we show that the N-HR peptide preferentially binds receptor-activated Env and that CD4 binding is sufficient for triggering conformational changes that allow the peptide to bind Env, results similar to those seen with the C-HR peptide. However, activation by both CD4 and chemokine receptors further enhances Env binding by both peptides. We also show that a nonconservative mutation in the N-HR of gp41 abolishes C-HR peptide but not N-HR peptide binding to gp41. These results indicate that there are two distinct sites in receptor-activated Env that are potential targets for drug or vaccine development.
He
Yong
Y
Center for Biologics Evaluation and Research, Food and Drug Administration, National Institutes of Health, Bethesda, Maryland 20892, USA.
Vassell
Russell
R
Zaitseva
Marina
M
Nguyen
Nga
N
Yang
Zhongning
Z
Weng
Yongkai
Y
Weiss
Carol D
CD
D000595:Amino Acid Sequence; D015704:CD4 Antigens / Q000378:metabolism; D015700:HIV Envelope Protein gp41 / Q000737:chemistry / Q000378:metabolism*; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D008561:Membrane Fusion; D008969:Molecular Sequence Data; D019718:Receptors, CXCR4 / Q000502:physiology; D020449:Repetitive Sequences, Amino Acid
D015704:CD4 Antigens; D015700:HIV Envelope Protein gp41; D019718:Receptors, CXCR4