Cyclin T1 stabilizes expression levels of HIV-1 Tat in cells.
Transcription from HIV-1 proviral DNA is a rate-determining step for HIV-1 replication. Interaction between the cyclin T1 (CycT1) subunit of positive transcription elongation factor b (P-TEFb) and the Tat transactivator protein of HIV-1 is crucial for viral transcription. CycT1 also interacts directly with the transactivation-responsive element (TAR) located on the 5'end of viral mRNA, as well as with Tat through the Tat-TAR recognition motif (TRM). These molecular interactions represent a critical step for stimulation of HIV transcription. Thus, Tat and CycT1 are considered to be feasible targets for the development of novel anti-HIV therapies. In this study, we demonstrate that CycT1 is positively involved in the Tat protein stability. Selective degradation of CycT1 by small interfering RNA (siRNA) culminated in proteasome-mediated degradation of Tat and eventual inhibition of HIV-1 gene expression. We noted that the siRNA-mediated knockdown of CycT1 could inhibit HIV-1 transcription without affecting cell viability and Tat mRNA levels. These findings clearly indicate that CycT1 is a feasible therapeutic target, and inactivation or depletion of CycT1 should effectively inhibit HIV replication by destabilizing Tat and suppressing Tat-mediated HIV transcription.
Imai
Kenichi
K
Department of Molecular and Cellular Biology, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Asamitsu
Kaori
K
Victoriano
Ann Florence B
AF
Cueno
Marni E
ME
Fujinaga
Koh
K
Okamoto
Takashi
T
D056906:Cyclin T / Q000235:genetics / Q000378:metabolism*; D015536:Down-Regulation; D006801:Humans; D019169:Jurkat Cells; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D055550:Protein Stability; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000235:genetics* / Q000378:metabolism
D056906:Cyclin T; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D054322:tat Gene Products, Human Immunodeficiency Virus; D046988:Proteasome Endopeptidase Complex