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Journal of Virology, December 2001, p. 11534-11543, Vol. 75, No. 23
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.23.11534-11543.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Unique Monoclonal Antibody Recognizing the Third Extracellular Loop of CXCR4 Induces Lymphocyte Agglutination and Enhances Human Immunodeficiency Virus Type 1-Mediated Syncytium Formation and Productive Infection

Reiko Tanaka,1 Atsushi Yoshida,1 Tsutomu Murakami,1 Eishi Baba,1 Julliane Lichtenfeld,1 Takeru Omori,1 Tohru Kimura,2 Naomi Tsurutani,3 Nobutaka Fujii,4 Zi-Xuan Wang,5 Stephen C. Peiper,5 Naoki Yamamoto,3 and Yuetsu Tanaka1,*

Department of Infectious Disease and Immunology, Okinawa-Asia Research Center of Medical Science, Faculty of Medicine, University of the Ryukyus, Okinawa,1 Department of Molecular Cell Biology, Research Institute for Microbial Diseases, Osaka University, Osaka,2 Department of Molecular Virology, Bio-Response, Graduate School, Tokyo Medical and Dental University, Tokyo,3 and Graduate School of Pharmaceutical Science, Kyoto University, Kyoto,4 Japan, and Henry Vogt Cancer Research Institute, University of Louisville, Louisville, Kentucky5

Received 8 May 2001/Accepted 28 August 2001

To increase insight into the structural basis of CXCR4 utilization in human immunodeficiency virus type 1 (HIV-1) infection, a new generation of three monoclonal antibodies (MAbs) was developed in WKA rats. The A80 MAb, which binds an epitope in the third extracellular loop (ECL3) of CXCR4, has unique biologic properties that provide novel insights into CXCR4 function. This agent enhanced syncytium formation in activated human peripheral blood mononuclear cells (PBMC) infected with X4 or R5 and CEM cells infected with X4 HIV-1 strains. Exposure to A80 increased the productive infection of activated CD4+ T cells and CEM cells with R5 and X4 viruses, respectively. This antibody uniquely induced agglutination of PBMC and CEM cells but did not activate calcium mobilization. Agglutination induced by A80 was inhibited by stromal cell-derived factor 1, T22, and phorbol 12-myristate 13-acetate but was not significantly altered by pretreatment of cells with pertussis toxin, wortmannin, or MAbs to LFA-1, ICAM-1, ICAM-2, and ICAM-3. The binding of the A145 and A120 MAbs was mapped to the N-terminal extracellular domain and a conformational epitope involving ECL1 and ECL2, respectively. Both of these MAbs inhibited HIV-1 infection and lacked the novel properties of A80. These results suggest a new role for CXCR4 in homologous lymphocyte adhesion that is ligand independent and in HIV-1 infection.

* Corresponding author. Mailing address: Department of Infectious Disease and Immunology, Okinawa-Asia Research Center of Medical Science, Faculty of Medicine, University of the Ryukyus, Uehara 207, Nishihara, Okinawa 903-0215, Japan. Phone: 81-98-895-1202. Fax: 81-98-895-1437. E-mail: yuetsu{at}ma.kcom.ne.jp.

Journal of Virology, December 2001, p. 11534-11543, Vol. 75, No. 23
0022-538X/01/$04.00+0   DOI: 10.1128/JVI.75.23.11534-11543.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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