Tyrosine-sulfated V2 peptides inhibit HIV-1 infection via coreceptor mimicry

EBioMedicine

Xavier Ambroggio¹  Michael A. Dolan¹  Darrell E. Hurt¹  Brian F. Volkman²  Francis C. Peterson²  Luca De Gioia³  Qingbo Liu⁴  Huiyi Miao⁴  Paolo Lusso⁴  Peng Zhang⁴  Donald Van Ryk⁴  Raffaello Cimbro⁴  Christina Guzzo⁴ 

[1] Bioinformatics and Computational Biosciences Branch, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA;Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI 53226, USA;Department of Biotechnology and Biosciences, University of Milano-Bicocca, Piazza della Scienza 2, 20126 Milan, Italy;Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, NIH, Bethesda, MD 20892, USA;

关键词: HIV-1;    Envelope;    Trimer;    Coreceptors;    Molecular mimicry;    Peptides;    Inhibitors;    Immune evasion;   

DOI  :  10.1016/j.ebiom.2016.06.037

来源: DOAJ

【 摘 要 】

Tyrosine sulfation is a post-translational modification that facilitates protein-protein interaction. Two sulfated tyrosines (Tys173 and Tys177) were recently identified within the second variable (V2) loop of the major HIV-1 envelope glycoprotein, gp120, and shown to contribute to stabilizing the intramolecular interaction between V2 and the third variable (V3) loop. Here, we report that tyrosine-sulfated peptides derived from V2 act as structural and functional mimics of the CCR5 N-terminus and potently block HIV-1 infection. Nuclear magnetic and surface plasmon resonance analyses indicate that a tyrosine-sulfated V2 peptide (pV2α-Tys) adopts a CCR5-like helical conformation and directly interacts with gp120 in a CD4-dependent fashion, competing with a CCR5 N-terminal peptide. Sulfated V2 mimics, but not their non-sulfated counterparts, inhibit HIV-1 entry and fusion by preventing coreceptor utilization, with the highly conserved C-terminal sulfotyrosine, Tys177, playing a dominant role. Unlike CCR5 N-terminal peptides, V2 mimics inhibit a broad range of HIV-1 strains irrespective of their coreceptor tropism, highlighting the overall structural conservation of the coreceptor-binding site in gp120. These results document the use of receptor mimicry by a retrovirus to occlude a key neutralization target site and provide leads for the design of therapeutic strategies against HIV-1.

【 授权许可】

Unknown