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J Biol Chem 2005 Aug 19;280(33):29570-7

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 LR, Abdoulaeva G, Antonsson L, Owman C, Platt EJ, Kabat D, Andersen JF, Sher A

Golding H, US FDA, Div Viral Prodat & Res, Bethesda, MD 20892 USA US FDA, Div Viral Prodat & Res, Bethesda, MD 20892 USA US FDA, Core Facil, Ctr Biol Evaluat & Res, Bethesda, MD 20892 USA NIAID, Parasit Dis Lab, NIH, Bethesda, MD 20892 USA NIAID, Lab Malaria & Vector Res, NIH, Bethesda, MD 20892 USA Div Mol Neurobiol, SE-22184 Lund, Sweden Oregon Hlth Sci Univ, Portland, OR 97239 USA

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 HIV co-receptor CCR5, and inhibits fusion and infection of T cells and macrophages by R5 viruses, but not with X4 viruses. We recently identified structural determinants of C-18 required for anti-HIV activity (Yarovinsky et al., 2004 JBC 51:53635-53642). In the current study, 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 (2-19). These experiments identified a critical role for CCR5 amino-terminus in C-18 binding and anti-HIV activity. Studies with a large panel of CCR5 N-terminus peptides, including Tyr-sulfated analogues, truncated peptides, and alanine-scanning mutants, suggested that each of the amino acids 12- 17 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 since the same CCR5 N-terminal region was previously shown to play a key role in binding of HIV-1 envelope glycoproteins. The elucidation of the functional C-18- binding mechanism may help in rational design of novel anti-viral agents against HIV.


Category: Journal Article
PubMed ID: #15975927
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2011-10-04 Entry Last Modified: 2012-08-29
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