Recruitment of a protein complex containing Tat and cyclin T1 to TAR governs the species specificity of HIV-1 Tat.
Human cyclin T1 (hCycT1), a major subunit of the essential elongation factor P-TEFb, has been proposed to act as a cofactor for human immunodeficiency virus type 1 (HIV-1) Tat. Here, we show that murine cyclin T1 (mCycT1) binds the activation domain of HIV-1 Tat but, unlike hCycT1, cannot mediate Tat function because it cannot be recruited efficiently to TAR. In fact, overexpression of mCycT1, but not hCycT1, specifically inhibits Tat-TAR function in human cells. This discordant phenotype results from a single amino acid difference between hCycT1 and mCycT1, a tyrosine in place of a cysteine at residue 261. These data indicate that the ability of Tat to recruit CycT1/P-TEFb to TAR determines the species restriction of HIV-1 Tat function in murine cells and therefore demonstrate that this recruitment is a critical function of the Tat protein.
Bieniasz
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Howard Hughes Medical Institute and Department of Genetics, Box 3025, Room 426, CARL Building, Duke University Medical Center, Research Drive, Durham, NC 27710, USA.
Grdina
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Bogerd
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Cullen
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D000595:Amino Acid Sequence; D000818:Animals; D001483:Base Sequence; D002461:Cell Line, Transformed; D003001:Cloning, Molecular; D056906:Cyclin T; D016213:Cyclins / Q000235:genetics / Q000378:metabolism*; D018076:DNA, Complementary; D015696:Gene Products, tat / Q000235:genetics / Q000378:metabolism*; D016325:HIV Long Terminal Repeat; D015497:HIV-1 / Q000235:genetics*; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D013045:Species Specificity; D054322:tat Gene Products, Human Immunodeficiency Virus
C503684:CCNT1 protein, human; C503685:Ccnt1 protein, mouse; D056906:Cyclin T; D016213:Cyclins; D018076:DNA, Complementary; D015696:Gene Products, tat; D054322:tat Gene Products, Human Immunodeficiency Virus