CCR5 N-terminal region plays a critical role in HIV-1 inhibition by Toxoplasma gondii-derived cyclophilin-18

Hana Golding, Surender Khurana, Felix Yarovinsky, Lisa R. King, Galina Abdoulaeva, Liselotte Antonsson, Christer Owman, Emily J. Platt, David Kabat, John F. Andersen, Alan Sher

Research output: Contribution to journalArticle

10 Scopus citations

Abstract

Molecular mimicry of chemokine ligands has been described for several pathogens. Toxoplasma gondii produces a protein, cyclophilin-18 (C-18), which binds to the human immunodeficiency virus (HIV) co-receptor CCR5 and inhibits fusion and infection of T cells and macrophages by R5 viruses but not by X4 viruses. We recently identified structural determinants of C-18 required for anti-HIV activity (Yarovinsky, F., Andersen, J. F., King, L. R., Caspar, P., Aliberti, J., Golding, H., and Sher, A. (2004) J. Biol. Chem. 279, 53635-53642). Here we have elucidated the fine specificity of CCR5 residues involved in binding and HIV inhibitory potential of C-18. To delineate the regions of CCR5 involved in C-18 binding, we analyzed C-18 inhibition of cells expressing CXCR4/ CCR5 chimeric receptors and CCR5 with a truncated N terminus (Δ2-19). These experiments identified a critical role for the N terminus of CCR5 in C-18 binding and anti-HIV activity. Studies with a large panel of CCR5 N-terminal peptides, including Tyr-sulfated analogues, truncated peptides, and alanine-scanning mutants, suggested that each of the 12-17 amino acids in the N terminus of CCR5 are essential for C-18 binding and inhibitory activity. Tyr sulfation did not improve C-18 reactivity. This finding is of interest because the same CCR5 N-terminal region was shown previously to play a key role in binding of HIV-1 envelope glycoproteins. The elucidation of the functional C-18-binding mechanism may help in the rational design of novel antiviral agents against HIV.

Original languageEnglish (US)
Pages (from-to)29570-29577
Number of pages8
JournalJournal of Biological Chemistry
Volume280
Issue number33
DOIs
StatePublished - Aug 19 2005

    Fingerprint

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Golding, H., Khurana, S., Yarovinsky, F., King, L. R., Abdoulaeva, G., Antonsson, L., Owman, C., Platt, E. J., Kabat, D., Andersen, J. F., & Sher, A. (2005). CCR5 N-terminal region plays a critical role in HIV-1 inhibition by Toxoplasma gondii-derived cyclophilin-18. Journal of Biological Chemistry, 280(33), 29570-29577. https://doi.org/10.1074/jbc.M500236200