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J Virol, August 1998, p. 6430-6436, Vol. 72, No. 8
Departments of
Microbiology1 and
Medicine,2 Columbia University,
College of Physicians and Surgeons, New York, New York 10032
Received 19 November 1997/Accepted 25 April 1998
Human immunodeficiency virus type 1 (HIV-1) Gag and the cellular
protein cyclophilin A form an essential complex in the virion core:
virions produced by proviruses encoding Gag mutants with decreased
cyclophilin A affinity exhibit attenuated infectivity, as do virions
produced in the presence of the competitive inhibitor cyclosporine. The A224E Gag mutant has no effect on cyclophilin A affinity but renders HIV-1 replication cyclosporine
resistant in Jurkat T cells. In contrast, A224E mutant virus is dead in H9 T cells, although replication is rescued by cyclosporine or by
expression in cis of a Gag mutant that decreases
cyclophilin A-affinity. The observation that disruption of the
Gag-cyclophilin A interaction rescues A224E mutant replication in H9
cells prompted experiments which revealed that, relative to Jurkat
cells, H9 cells express greater quantities of
cyclophilin A. The resulting larger quantity of cyclophilin A
shown to be packaged into virions produced by H9 cells is presumably
disruptive to the A224E mutant virion core. Further evidence that
increased cyclophilin A expression in H9 cells is of functional
relevance was provided by the finding that Gag mutants with decreased
cyclophilin A affinity are dead in Jurkat cells but capable of
replication in H9 cells. Similarly, cyclosporine concentrations which
inhibit wild-type HIV-1 replication in Jurkat cells stimulate HIV-1
replication in H9 cells. These results suggest that HIV-1 virion
infectivity imposes narrow constraints upon cyclophilin A stoichiometry
in virions and that infectivity is finely tuned by host cyclophilin A
expression levels.
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Human Immunodeficiency Virus Type 1 Replication Is
Modulated by Host Cyclophilin A Expression Levels
*
Corresponding author. Mailing address: Departments of
Microbiology and Medicine, Columbia University, College of Physicians and Surgeons, 701 W. 168th St., New York, NY 10032. Phone: (212) 305-8706. Fax: (212) 305-0333. E-mail:
Luban{at}cuccfa.ccc.columbia.edu.
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