Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

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Golding, H. et al.

Golding, Khurana, Yarovinsky, King, Abdoulaeva, Antonsson, Owman, Platt, Kabat, Andersen, Sher,

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

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 (Delta2-19). 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.[1]

References

CCR5 N-terminal region plays a critical role in HIV-1 inhibition by Toxoplasma gondii-derived cyclophilin-18. 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. J. Biol. Chem. (2005) [Pubmed]

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