The N-terminal domain of APJ, a CNS-based coreceptor for HIV-1, is essential for its receptor function and coreceptor activity

被引:53
作者
Zhou, NM
Zhang, XL
Fan, XJ
Argyris, E
Fang, JH
Acheampong, E
DuBois, GC
Pomerantz, RJ [1 ]
机构
[1] Jefferson Med Coll, Dept Med, Div Infect Dis & Environm Med, Ctr Human Virol & Biodef,Darrance H Hamilton, Philadelphia, PA 19107 USA
[2] Thomas Jefferson Univ, Kimmel Canc Ctr, Philadelphia, PA 19107 USA
关键词
APJ receptor; mutagenesis; apelin; signaling; HIV-1; CNS;
D O I
10.1016/j.virol.2003.08.026
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The human APJ, a G protein-coupled seven-transmembrane receptor, has been found to be dramatically expressed in the human central nervous system (CNS) and also to serve as a coreceptor for the entry of human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV). Studies with animal models suggested that APJ and its natural ligand, apelin, play an important role in the central control of body fluid homeostasis, and in regulation of blood pressure and cardiac contractility. In this study, we characterize the structural and functional determinants of the N-terminal domain of APJ in interactions with its natural ligand and HIV-1 envelope glycoprotein. We demonstrate that the second 10 residues of the N-terminal domain of APJ are critical for association with apelin, while the first 20 amino acids play an important role in supporting cell-cell fusion mediated by HIV-1 gp120. With site-directed mutagenesis, we have identified that the negatively charged amino acid residues Glu20 and Asp23 are involved in receptor and coreceptor functions, but residues Tyr10 and Tyr11 substantially contribute to coreceptor function for both T-tropic (CXCR4) and dual-tropic (CXCR4 and CCR5) HIV-1 isolates. Thus, this study provides potentially important information for further characterizing APJ-apelin functions in vitro and in vivo and designing small molecules for treatment of HIV-1 infection in the CNS. (C) 2003 Elsevier Inc. All rights reserved.
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收藏
页码:84 / 94
页数:11
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