Peptide ligands selected with CD4-induced epitopes on native dualtropic HIV-1 envelope proteins mimic extracellular coreceptor domains and bind to HIV-1 gp120 independently of coreceptor usage.

Journal of virology 2010 Jul 21; In press

Dervillez X, Klaukien V, Dürr R, Koch J, Kreutz A, Haarmann T, Stoll M, Lee D, Carlomagno T, Schnierle B, Möbius K, Königs C, Griesinger C, Dietrich U

Georg-Speyer-Haus, Institute for Biomedical Research, Paul-Ehrlich-Str. 42-44, 60596 Frankfurt, Germany; Max-Planck-Institute for Biophysical Chemistry, Am Fassberg 11, 37077 Göttingen, Germany; Paul-Ehrlich-Institute, Paul-Ehrlich-Str. 51-59, 63225 Lang

During HIV-1 entry, binding of the viral envelope glycoprotein gp120 to the cellular CD4 receptor triggers conformational changes resulting in exposure of new epitopes, the highly conserved CD4-induced (CD4i) epitopes that are essential for subsequent binding to chemokine receptors CCR5 or CXCR4. Due to their functional conservation, CD4i epitopes represent attractive viral targets for HIV-1 entry inhibition. The aim of this study was to select peptide ligands for CD4i epitopes on native dualtropic (R5X4) HIV-1 envelope (Env) glycoproteins by phage display. Using CD4 activated retroviral particles carrying Env from the R5X4 HIV-1 89.6 strain as target, we performed screenings of random peptide phage libraries under stringent selection conditions. Selected peptides showed partial identity with amino acids in the extracellular domains of CCR5/CXCR4 including motifs rich in tyrosines and aspartates at the N-terminus known to be important for gp120 binding. A synthetic peptide derivative (XD3) corresponding to the most frequently selected phage was optimized for Env binding on peptide arrays. Interestingly, the optimized peptide could bind specifically to gp120 derived from HIV-1 strains with different coreceptor usage, competed with binding of CD4i-specific monoclonal antibody (mAb) 17b and interfered with virus entry of both, a CCR5 using (R5) and a CXCR4 using (X4) Env pseudotyped virus. This peptide ligand therefore points at unique properties of CD4i epitopes shared by gp120 with different coreceptor usage and could thus serve to provide new insight into the conserved structural details essential for coreceptor binding for further drug development.

Keywords: HIV