Cyclophilin interactions with incoming human immunodeficiency virus type 1 capsids with opposing effects on infectivity in human cells.
Cyclophilin A (CypA) is a peptidyl-prolyl isomerase that binds to the capsid protein (CA) of human immunodeficiency virus type 1 (HIV-1) and by doing so facilitates HIV-1 replication. Although CypA is incorporated into HIV-1 virions by virtue of CypA-Gag interactions that occur during virion assembly, in this study we show that the CypA-CA interaction that occurs following the entry of the viral capsid into target cells is the major determinant of CypA's effects on HIV-1 replication. Specifically, by using normal and CypA-deficient Jurkat cells, we demonstrate that the presence of CypA in the target and not the virus-producing cell enhances HIV-1 infectivity. Moreover, disruption of the CypA-CA interaction with cyclosporine A (CsA) inhibits HIV-1 infectivity only if the target cell expresses CypA. The effect of CsA on HIV-1 infection of human cells varies according to which particular cell line is used as a target, and CA mutations that confer CsA resistance and dependence exert their effects only if target cells, and not if virus-producing cells, are treated with CsA. The differential effects of CsA on HIV-1 infection in different human cells appear not to be caused by polymorphisms in the recently described retrovirus restriction factor TRIM5alpha. We speculate that CypA and/or CypA-related proteins affect the fate of incoming HIV-1 capsid either directly or by modulating interactions with unidentified host cell factors.
Hatziioannou
Theodora
T
Aaron Diamond AIDS Research Center and Rockefeller University, New York, New York 10021, USA.
Perez-Caballero
David
D
Cowan
Simone
S
Bieniasz
Paul D
PD
D000818:Animals; D000090103:Antiviral Restriction Factors; D002213:Capsid / Q000378:metabolism*; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism; D002460:Cell Line; D021984:Cyclophilin A / Q000235:genetics / Q000378:metabolism*; D016572:Cyclosporine / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000378:metabolism / Q000472:pathogenicity*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D009154:Mutation; D019696:Peptidylprolyl Isomerase / Q000235:genetics / Q000378:metabolism*; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases; D014771:Virion / Q000378:metabolism; D014779:Virus Replication
D000090103:Antiviral Restriction Factors; D036022:Capsid Proteins; D002352:Carrier Proteins; D000070584:Tripartite Motif Proteins; D016572:Cyclosporine; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases; D021984:Cyclophilin A; D019696:Peptidylprolyl Isomerase