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Originally published In Press as doi:10.1074/jbc.M001917200 on April 21, 2000
J. Biol. Chem., Vol. 275, Issue 27, 20288-20294, July 7, 2000
Coreceptor Function of Mutant Human CD4 Molecules without
Affinity to gp120 of Human Immunodeficiency Virus*
Makoto
Tachibana ,
Mushtaq A.
Siddiqi,
Yuko
Ikegami,
Koji
Eshima§,
Yoshiko
Shirota-Someya,
Satoko
Tahara-Hanaoka¶,
Atsushi
Koito¶,
Misao
Iizuka§, and
Nobukata
Shinohara§
From the Department of Immunology, Mitsubishi Kasei
Institute of Life Sciences, Machida, Tokyo 194, the ¶ Department
of Immunology, Institute of Basic Medial Sciences and Center for
Tsukuba Advanced Research Alliance, Tsukuba University, Ibaraki
305-8577, and the § Department of Immunology, Kitasato
University School of Medicine, Sagamihara, Kanagawa 228-8555, Japan
Despite extensive mutational studies on the human
CD4 molecule and its affinity to human immunodeficiency virus (HIV)
envelope glycoprotein gp120, coreceptor functions of such mutant
molecules have only been examined by indirect measurement of their
affinity to class II major histocompatibility complex (MHC) molecules. In this report, coreceptor functions of mutant human CD4 molecules, which have no or reduced affinity to an HIV envelope protein, gp120,
were assessed in a murine T cell receptor/class II MHC recognition
system. The substitution of human C"  strand with the murine
homologous segment resulted in the loss of the coreceptor function as
well as in the complete loss of gp120 binding capacity, corroborating
the consensus that Phe-43 in C" strand plays crucial roles in both
situations. However, simultaneous replacement of the C'-C" loop along
with the C" strand by homologous murine segments rescued the
coreceptor function, whereas gp120 binding capacity remained negative.
Further analysis indicated that insertion of lysine between Gly-41 and
Ser-42 can partially compensate for the coreceptor function lost by the
Phe-43  Val mutation. Although the coreceptor function of these
mutant CD4 molecules in a human T cell recognition system is yet to be
determined, these observations necessitate a re-evaluation of the role
played by Phe-43 in coreceptor function. Examination of the
sensitivities of the mutant CD4 molecules expressed on HeLa cells to
infection by a T cell-tropic HIV-1 strain indicated that only those
mutants that had completely lost gp120 binding capacity were resistant
to the infection. All mutants having whole C" substitution,
irrespective of additional substitutions or their coreceptor functions,
were resistant to the infection.
*
This work has been supported by the grant from The Project
to Promote Development of Anti-AIDS Pharmaceuticals of The Japan Health
Sciences Foundation.The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
To whom correspondence should be addressed: Dept. of
Immunology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 228-8555, Japan. Tel.: 81-42-778-8834 (and -9266);
Fax: 81-42-778-8441; E-mail: nobu@med.kitasato-u.ac.jp.
Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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Copyright © 2000 by the American Society for Biochemistry and Molecular Biology.
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