Abstract
HIV-1 depends on host-cell resources for replication, access to which may be limited to a particular phase of the cell cycle. The HIV-encoded proteins Vpr (viral protein R) and Vif (viral infectivity factor) arrest cells in the G₂ phase; however, alteration of other cell-cycle phases has not been reported. We show that Vif drives cells out of G₁ and into the S phase. The effect of Vif on the G₁- to-S transition is distinct from its effect on G₂, because G₂ arrest is Cullin5-dependent, whereas the G₁- to-S progression is Cullin5-independent. Using mass spectrometry, we identified 2 novel cellular partners of Vif, Brd4 and Cdk9, both of which are known to regulate cell-cycle progression. We confirmed the interaction of Vif and Cdk9 by immunoprecipitation and Western blot, and showed that small interfering RNAs (siRNAs) specific for Cdk9 inhibit the Vif-mediated G₁- to-S transition. These data suggest that Vif regulates early cell-cycle progression, with implications for infection and latency.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Cycle / drug effects
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Cell Cycle / genetics*
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Cell Cycle / physiology
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Cell Proliferation* / drug effects
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Cullin Proteins / genetics
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Cullin Proteins / metabolism
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Cullin Proteins / physiology
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Cyclin-Dependent Kinase 9 / antagonists & inhibitors
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Cyclin-Dependent Kinase 9 / genetics
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Cyclin-Dependent Kinase 9 / metabolism
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G1 Phase / drug effects
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G1 Phase / genetics
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G1 Phase / physiology
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Gene Expression Regulation / drug effects
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HIV Infections / genetics
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HIV Infections / metabolism
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HIV Infections / pathology
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HIV-1 / genetics
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HIV-1 / physiology
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HeLa Cells
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Humans
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Models, Biological
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Mutant Proteins / genetics
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Mutant Proteins / metabolism
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Protein Binding / drug effects
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Protein Binding / physiology
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RNA, Small Interfering / pharmacology
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S Phase / drug effects
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S Phase / genetics
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S Phase / physiology
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Transfection
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Virus Latency / drug effects
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Virus Latency / genetics
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vif Gene Products, Human Immunodeficiency Virus / genetics
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vif Gene Products, Human Immunodeficiency Virus / metabolism
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vif Gene Products, Human Immunodeficiency Virus / physiology*
Substances
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CUL5 protein, human
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Cullin Proteins
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Mutant Proteins
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RNA, Small Interfering
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vif Gene Products, Human Immunodeficiency Virus
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CDK9 protein, human
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Cyclin-Dependent Kinase 9