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Journal of Virology, September 1999, p. 7489-7496, Vol. 73, No. 9
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

Inhibitory Mechanism of the CXCR4 Antagonist T22 against Human Immunodeficiency Virus Type 1 Infection

Tsutomu Murakami,1,dagger Tian-Yuan Zhang,2 Yoshio Koyanagi,1 Yuetsu Tanaka,3 Jin Kim,4 Yoichi Suzuki,1 Shigeru Minoguchi,5,9 Hirokazu Tamamura,6 Michinori Waki,7 Akiyoshi Matsumoto,7 Nobutaka Fujii,6 Hisatoshi Shida,5 James A. Hoxie,8 Stephen C. Peiper,2 and Naoki Yamamoto1,*

Department of Microbiology and Molecular Virology, Faculty of Medicine, Tokyo Medical and Dental University, Bunkyo-ku, Tokyo 113-8519,1 University of the Ryukyus, Okinawa 903-0215,3 Institute for Virus Research, Kyoto University, Kyoto 606-01,5 Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto 606-8501,6 Seikagaku Corporation, Tokyo 103,7 and Department of Medical Chemistry, Faculty of Medicine, Kyoto University, Sakyo-ku, Kyoto 606,9 Japan; University of Louisville, Louisville, Kentucky 402022; Genentech, South San Francisco, California 940804; and University of Pennsylvania, Philadelphia, Pennsylvania 191048

Received 8 February 1999/Accepted 28 May 1999

We recently reported that a cationic peptide, T22 ([Tyr5,12, Lys7]-polyphemusin II), specifically inhibits human immunodeficiency virus type 1 (HIV-1) infection mediated by CXCR4 (T. Murakami et al., J. Exp. Med. 186:1389-1393, 1997). Here we demonstrate that T22 effectively inhibits replication of T-tropic HIV-1, including primary isolates, but not of non-T-tropic strains. By using a panel of chimeric viruses between T- and M-tropic HIV-1 strains, viral determinants for T22 susceptibility were mapped to the V3 loop region of gp120. T22 bound to CXCR4 and interfered with stromal-cell-derived factor-1alpha -CXCR4 interactions in a competitive manner. Blocking of anti-CXCR4 monoclonal antibodies by T22 suggested that the peptide interacts with the N terminus and two of the extracellular loops of CXCR4. Furthermore, the inhibition of cell-cell fusion in cells expressing CXCR4/CXCR2 chimeric receptors suggested that determinants for sensitivity of CXCR4 to T22 include the three extracellular loops of the coreceptor.

* Corresponding author. Mailing address: Departments of Microbiology and Molecular Virology, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. Phone: 81-3-5803-5178. Fax: 81-3-5803-0124. E-mail: yamamoto.mmb{at}med.tmd.ac.jp.

dagger Present address: Laboratory of Molecular Microbiology, NIAID, NIH, Bethesda, MD 20892-0460.

Journal of Virology, September 1999, p. 7489-7496, Vol. 73, No. 9
0022-538X/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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