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J. Biol. Chem., Vol. 280, Issue 35, 30924-30934, September 2, 2005

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The Synthetic Peptide Derived from the NH₂-terminal Extracellular Region of an Orphan G Protein-coupled Receptor, GPR1, Preferentially Inhibits Infection of X4 HIV-1^*

Atsushi Jinno-Oue, Nobuaki Shimizu, Yasushi Soda, Atsushi Tanaka, Takahiro Ohtsuki, Dai Kurosaki, Yasuo Suzuki¶, and Hiroo Hoshino||

From the Department of Virology and Preventive Medicine, Gunma University Graduate School of Medicine, Showa-machi, Maebashi, Gunma 371-8511 and the ^¶Department of Biochemistry, University of Shizuoka School of Pharmaceutical Science, 52-1, Yada, Shizuoka 422-8526, Japan

Several G protein-coupled receptors (GPCRs) serve as co-receptors for entry of human immunodeficiency virus type 1 (HIV-1) into target cells. Here we report that a synthetic peptide derived from the NH₂-terminal extracellular region of an orphan GPCR, GPR1 (GPR1ntP-(1-27); MEDLEETLFEEFENYSYDLDYYSLESC), inhibited infection of not only an HIV-1 variant that uses GPR1 as a co-receptor, but also X4, R5, and R5X4 viruses. Among these HIV-1 strains tested, viruses that can utilize CXCR4 as their co-receptors were preferentially inhibited. Inhibition of early steps in X4 virus replication was also detected in the primary human peripheral blood lymphocytes. GPR1ntP-(1-27) directly interacted with recombinant X4 envelope glycoprotein (rgp120). This interaction was neither inhibited nor enhanced by the soluble CD4 (sCD4) but inhibited by the anti-third variable (V3) loop-specific monoclonal antibody and heparin known to bind to the V3 loop. Although the conformational changes in gp120, including the V3 loop, have been reported to be required for its interaction with a co-receptor after binding of gp120 to CD4, it has also been reported that the V3 loop is already exposed on the surface of virions before interaction with CD4. We found that GPR1ntP-(1-27) blocked binding of virus to the cells, and this peptide equally bound to rgp120 in the presence or absence of sCD4. Because we detected the binding of GPR1ntP-(1-27) to the highly purified virions even in the absence of sCD4, GPR1ntP-(1-27) probably recognized the V3 loop exposed on the virions, and this interaction was responsible for the anti-HIV-1 activity of GPR1ntP-(1-27).

Received for publication, January 6, 2005 , and in revised form, May 19, 2005.

^* This work was supported in part by grants-in-aid for Scientific Research and the 21st Century Centers of Excellence (COE) Program from the Ministry of Education, Culture, Sports, Science and Technology of Japan and by Core Research for Evolutional Science and Technology, Japan Science and Technology Corp. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Present address: Dept. of Hematology and Oncology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108-8639, Japan.

^|| To whom correspondence should be addressed: Tel.: 81-27-220-8000; Fax: 81-27-220-8006; E-mail: hoshino{at}med.gunma-u.ac.jp.

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