Target cell cyclophilin a modulates human immunodeficiency virus type 1 infectivity

被引:181
作者
Sokolskaja, E
Sayah, DM
Luban, J
机构
[1] Columbia Univ, Dept Microbiol, New York, NY 10032 USA
[2] Columbia Univ, Dept Med, New York, NY 10032 USA
关键词
D O I
10.1128/JVI.78.23.12800-12808.2004
中图分类号
Q93 [微生物学];
学科分类号
071005 ; 100705 ;
摘要
The peptidyl-prolyl isomerase cyclophilin A (CypA) increases the kinetics by which human immunodeficiency virus type 1 (HIV-1) spreads in tissue culture. This was conclusively demonstrated by gene targeting in human CD4(+) T cells, but the role of CypA in HIV-1 replication remains unknown. Though CypA binds to mature HIV-1 capsid protein (CA), it is also incorporated into nascent HIV-1 virions via interaction with the CA domain of the Gag polyprotein. These findings raised the possibility that CypA might act at multiple steps of the retroviral life cycle. Disruption of the CA-CypA interaction, either by the competitive inhibitor cyclosporine (CsA) or by mutation of CA residue G89 or P90, suggested that producer cell CypA was required for full virion infectivity. However, recent studies indicate that CypA within the target cell regulates HIV-1 infectivity by modulating Ref1- or Lv1-mediated restriction. To examine the relative contribution to HIV-1 replication of producer cell CypA and target cell CypA, we exploited multiple tools that disrupt the HIV-1 CA-CypA interaction. These tools included the drugs CsA, Melle (4)-CsA, and Sanglifehrin; CA mutants exhibiting decreased affinity for CypA or altered CypA dependence; HeLa cells with CypA knockdown by RNA interference; and Jurkat T cells homozygous for a deletion of the gene encoding CypA. Our results clearly demonstrate that target cell CypA, and not producer cell CypA, is important for HIV-1 CA-mediated function. Inhibition of HIV-1 infectivity resulting from virion production in the presence of CsA occurs independently of the CA-CypA interaction or even of CypA.
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页码:12800 / 12808
页数:9
相关论文
共 57 条
[21]   Active-site residues of cyclophilin A are crucial for its incorporation into human immunodeficiency virus type 1 virions [J].
Dorfman, T ;
Weimann, A ;
Borsetti, A ;
Walsh, CT ;
Gottlinger, HG .
JOURNAL OF VIROLOGY, 1997, 71 (09) :7110-7113
[22]   Sanglifehrins A, B, C and D, novel cyclophilin-binding compounds isolated from Streptomyces sp A92-308110 -: II.: Structure elucidation, stereochemistry and physico-chemical properties [J].
Fehr, T ;
Kallen, J ;
Oberer, L ;
Sanglier, JJ ;
Schilling, W .
JOURNAL OF ANTIBIOTICS, 1999, 52 (05) :474-479
[23]   Inhibition of HIV-1 replication by cyclosporine A or related compounds correlates with the ability to disrupt the Gag-cyclophilin A interaction [J].
Franke, EK ;
Luban, J .
VIROLOGY, 1996, 222 (01) :279-282
[24]   SPECIFIC INCORPORATION OF CYCLOPHILIN-A INTO HIV-1 VIRIONS [J].
FRANKE, EK ;
YUAN, HEH ;
LUBAN, J .
NATURE, 1994, 372 (6504) :359-362
[25]   HIV-1 Gag proteins: Diverse functions in the virus life cycle [J].
Freed, EO .
VIROLOGY, 1998, 251 (01) :1-15
[26]   2 CYTOPLASMIC CANDIDATES FOR IMMUNOPHILIN ACTION ARE REVEALED BY AFFINITY FOR A NEW CYCLOPHILIN - ONE IN THE PRESENCE AND ONE IN THE ABSENCE OF CSA [J].
FRIEDMAN, J ;
WEISSMAN, I .
CELL, 1991, 66 (04) :799-806
[27]   Crystal structure of human cyclophilin A bound to the amino-terminal domain of HIV-1 capsid [J].
Gamble, TR ;
Vajdos, FF ;
Yoo, SH ;
Worthylake, DK ;
Houseweart, M ;
Sundquist, WI ;
Hill, CP .
CELL, 1996, 87 (07) :1285-1294
[28]   ISOLATION AND PROPERTIES OF MOLONEY MURINE LEUKEMIA-VIRUS MUTANTS - USE OF A RAPID ASSAY FOR RELEASE OF VIRION REVERSE-TRANSCRIPTASE [J].
GOFF, S ;
TRAKTMAN, P ;
BALTIMORE, D .
JOURNAL OF VIROLOGY, 1981, 38 (01) :239-248
[29]   In vitro assembly properties of wild-type and cyclophilin-binding defective human immunodeficiency virus capsid proteins in the presence and absence of cyclophilin A [J].
Grättinger, M ;
Hohenberg, H ;
Thomas, D ;
Wilk, T ;
Müller, B ;
Kräusslich, HG .
VIROLOGY, 1999, 257 (01) :247-260
[30]   CYCLOPHILIN - A SPECIFIC CYTOSOLIC BINDING-PROTEIN FOR CYCLOSPORIN-A [J].
HANDSCHUMACHER, RE ;
HARDING, MW ;
RICE, J ;
DRUGGE, RJ .
SCIENCE, 1984, 226 (4674) :544-547