Human immunodeficiency virus type 1 replication is modulated by host cyclophilin A expression levels.
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.
Yin
L
L
Departments of Microbiology, Columbia University, College of Physicians and Surgeons, New York, New York 10032, USA.
Braaten
D
D
Luban
J
J
D000409:Alanine / Q000235:genetics / Q000378:metabolism; D015683:Gene Products, gag / Q000235:genetics / Q000378:metabolism; D016346:Gene Products, vif / Q000235:genetics / Q000378:metabolism; D018698:Glutamic Acid / Q000235:genetics / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics / Q000502:physiology*; D006801:Humans; D019169:Jurkat Cells; D016297:Mutagenesis, Site-Directed; D019696:Peptidylprolyl Isomerase / Q000378:metabolism* / Q000494:pharmacology; D011392:Proline / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014771:Virion; D014779:Virus Replication; D054320:vif Gene Products, Human Immunodeficiency Virus
D015683:Gene Products, gag; D016346:Gene Products, vif; D054320:vif Gene Products, Human Immunodeficiency Virus; D018698:Glutamic Acid; D011392:Proline; D019696:Peptidylprolyl Isomerase; D000409:Alanine