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Antimicrobial Agents and Chemotherapy, September 2003, p. 2810-2816, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.2810-2816.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Shikonin, a Component of Chinese Herbal Medicine, Inhibits Chemokine Receptor Function and Suppresses Human Immunodeficiency Virus Type 1

Xin Chen,1 Lu Yang,2 Ning Zhang,3 Jim A. Turpin,4 Robert W. Buckheit,2 Clay Osterling,5 Joost J. Oppenheim,3 and O. M. Zack Howard3*

Basic Research Program, SAIC-Frederick, Inc.,1 Laboratory of Molecular Immunoregulation, National Cancer Institute—Frederick, Frederick, Maryland 21702-1201,3 TherImmune Research Corporation, Gaithersburg, Maryland 20879,2 Howpin International Consulting, Frederick, Maryland 21703,4 Infectious Disease Research Department, Southern Research Institute, Frederick, Maryland 217015

Received 3 December 2002/ Returned for modification 20 February 2003/ Accepted 13 June 2003

Shikonin is a major component of zicao (purple gromwell, the dried root of Lithospermum erythrorhizon), a Chinese herbal medicine with various biological activities, including inhibition of human immunodeficiency virus (HIV) type 1 (HIV-1). G protein-coupled chemokine receptors are used by HIV-1 as coreceptors to enter the host cells. In this study, we assessed the effects of shikonin on chemokine receptor function and HIV-1 replication. The results showed that, at nanomolar concentrations, shikonin inhibited monocyte chemotaxis and calcium flux in response to a variety of CC chemokines (CCL2 [monocyte chemoattractant protein 1], CCL3 [macrophage inflammatory protein 1{alpha}], and CCL5 [regulated upon activation, normal T-cell expressed and secreted protein]), the CXC chemokine (CXCL12 [stromal cell-derived factor 1{alpha}]), and classic chemoattractants (formylmethionyl-leucine-phenylalanine and complement fraction C5a). Shikonin down-regulated surface expression of CCR5, a primary HIV-1 coreceptor, on macrophages to a greater degree than the other receptors (CCR1, CCR2, CXCR4, and the formyl peptide receptor) did. CCR5 mRNA expression was also down-regulated by the compound. Additionally, shikonin inhibited the replication of a multidrug-resistant strain and pediatric clinical isolates of HIV in human peripheral blood mononuclear cells, with 50% inhibitory concentrations (IC50s) ranging from 96 to 366 nM. Shikonin also effectively inhibited the replication of the HIV Ba-L isolate in monocytes/macrophages, with an IC50 of 470 nM. Our results suggest that the anti-HIV and anti-inflammatory activities of shikonin may be related to its interference with chemokine receptor expression and function. Therefore, shikonin, as a naturally occurring, low-molecular-weight pan-chemokine receptor inhibitor, constitutes a basis for the development of novel anti-HIV therapeutic agents.

* Corresponding author. Mailing address: Laboratory of Molecular Immunoregulation, National Cancer Institute—Frederick, B.O. Box B, Bldg. 560/Rm. 31-19, Frederick, MD 21702-1201. Phone: (301) 846-1347. Fax: (301) 846-6752. E-mail: howardz{at}mail.ncifcrf.gov.

Antimicrobial Agents and Chemotherapy, September 2003, p. 2810-2816, Vol. 47, No. 9
0066-4804/03/$08.00+0     DOI: 10.1128/AAC.47.9.2810-2816.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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