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

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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 (Delta 2-19). 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.

Details

Authors
  • H Golding
  • S Khurana
  • F Yarovinsky
  • L R King
  • G Abdoulaeva
  • Liselotte Antonsson
  • Christer Owman
  • EJ Platt
  • D Kabat
  • J F Andersen
  • A Sher
Organisations
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Pharmacology and Toxicology
Original languageEnglish
Pages (from-to)29570-29577
JournalJournal of Biological Chemistry
Volume280
Issue number33
Publication statusPublished - 2005
Publication categoryResearch
Peer-reviewedYes