title: Inhibition of HIV-1 transcription and replication by a newly identified cyclin T1 splice variant.
abstract: A variety of cellular factors participates in the HIV-1 life cycle. Among them is the well characterized cyclin T1 (CYCT1). CycT1 binds to cyclin-dependent kinase 9 (CDK9) and forms the positive transcription elongation factor-b (P-TEFb). P-TEFb is then recruited by HIV-1 TAT to the HIV-1 long terminal repeat (LTR) promoter and subsequently leads to phosphorylation of the C-terminal domain of RNA polymerase II (pol II), enhanced processivity of pol II, and transcription of a full-length HIV-1 RNA. In this study, we report the identification of a new CYCT1 splice variant, designated as CYCT1b, and accordingly we renamed CYCT1 as CYCT1a. CYCT1b was detected in several cell lines, including primary human CD4 T cells, and its expression was subject to cell cycle regulation. Similar to CYCT1a, CYCT1b was primarily localized in the nucleus. CYCT1b expression was found to be inversely correlated with HIV-1 gene expression and replication. This inverse correlation appeared to involve TAT transactivation, CDK9 binding, and subsequent recruitment of P-TEFb to the HIV-1 LTR promoter and pol II C-terminal domain phosphorylation. In agreement with these findings, CYCT1b expression led to direct inhibition of TAT-transactivated transcription of the HIV-1 LTR promoter. Taken together, these results show that the newly identified CYCT1b splice variant inhibits HIV-1 transcription and may provide new clues for the development of anti-HIV strategies.
authors.affiliation: State Key Laboratory of Virology and Modern Virology Research Center, Wuhan University College of Life Sciences, 430072 Wuhan, China; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Guozhen
authors.initials: G
authors.lastname: Gao
authors.affiliation: State Key Laboratory of Virology and Modern Virology Research Center, Wuhan University College of Life Sciences, 430072 Wuhan, China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Wu
authors.affiliation: State Key Laboratory of Virology and Modern Virology Research Center, Wuhan University College of Life Sciences, 430072 Wuhan, China.
authors.forename: Jieqiong
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202.
authors.forename: Mingfeng
authors.initials: M
authors.lastname: He
authors.affiliation: Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, Indiana 46202; Center for AIDS Research, Indiana University School of Medicine, Indianapolis, Indiana 46202; University of North Texas Health Science Center, Fort Worth, Texas 76107. Electronic address: johnny.he@unthsc.edu.
authors.forename: Johnny J
authors.initials: JJ
authors.lastname: He
authors.affiliation: State Key Laboratory of Virology and Modern Virology Research Center, Wuhan University College of Life Sciences, 430072 Wuhan, China; Institute of Medical Virology, Wuhan University School of Medicine, 430071 Wuhan, China. Electronic address: dguo@whu.edu.cn.
authors.forename: Deyin
authors.initials: D
authors.lastname: Guo
mesh_terms: D017398:Alternative Splicing; D000595:Amino Acid Sequence; D001483:Base Sequence; D056906:Cyclin T / Q000235:genetics* / Q000378:metabolism; D020869:Gene Expression Profiling; D015967:Gene Expression Regulation, Viral; D057809:HEK293 Cells; D015497:HIV-1 / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008969:Molecular Sequence Data; D016366:Open Reading Frames; D010766:Phosphorylation; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D020798:Two-Hybrid System Techniques; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: C503684:CCNT1 protein, human; D056906:Cyclin T; D020033:Protein Isoforms; D012333:RNA, Messenger; D054322:tat Gene Products, Human Immunodeficiency Virus
keywords: Cyclins; Gene Regulation; HIV-1; HIV-1 Tat; RNA Polymerase II; Transcription