Cyclin T1-dependent genes in activated CD4 T and macrophage cell lines appear enriched in HIV-1 co-factors.
HIV-1 is dependent upon cellular co-factors to mediate its replication cycle in CD4(+) T cells and macrophages, the two major cell types infected by the virus in vivo. One critical co-factor is Cyclin T1, a subunit of a general RNA polymerase II elongation factor known as P-TEFb. Cyclin T1 is targeted directly by the viral Tat protein to activate proviral transcription. Cyclin T1 is up-regulated when resting CD4(+) T cells are activated and during macrophage differentiation or activation, conditions that are also necessary for high levels of HIV-1 replication. Because Cyclin T1 is a subunit of a transcription factor, the up-regulation of Cyclin T1 in these cells results in the induction of cellular genes, some of which might be HIV-1 co-factors. Using shRNA depletions of Cyclin T1 and transcriptional profiling, we identified 54 cellular mRNAs that appear to be Cyclin T1-dependent for their induction in activated CD4(+) T Jurkat T cells and during differentiation and activation of MM6 cells, a human monocytic cell line. The promoters for these Cyclin T1-dependent genes (CTDGs) are over-represented in two transcription factor binding sites, SREBP1 and ARP1. Notably, 10 of these CTDGs have been reported to be involved in HIV-1 replication, a significant over-representation of such genes when compared to randomly generated lists of 54 genes (p value<0.00021). The results of siRNA depletion and dominant-negative protein experiments with two CTDGs identified here, CDK11 and Casein kinase 1 gamma 1, suggest that these genes are involved either directly or indirectly in HIV-1 replication. It is likely that the 54 CTDGs identified here include novel HIV-1 co-factors. The presence of CTDGs in the protein space that was available for HIV-1 to sample during its evolution and acquisition of Tat function may provide an explanation for why CTDGs are enriched in viral co-factors.
Yu
Wendong
W
Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, Texas, United States of America.
Ramakrishnan
Rajesh
R
Wang
Yan
Y
Chiang
Karen
K
Sung
Tzu-Ling
TL
Rice
Andrew P
AP
D001665:Binding Sites; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology* / Q000821:virology*; D047389:Casein Kinase I / Q000378:metabolism; D056906:Cyclin T; D018844:Cyclin-Dependent Kinases / Q000378:metabolism; D016213:Cyclins / Q000378:metabolism*; D015967:Gene Expression Regulation, Viral; D005799:Genes, Dominant; D015497:HIV-1 / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008213:Lymphocyte Activation; D008264:Macrophages / Q000166:cytology* / Q000821:virology*; D009000:Monocytes / Q000166:cytology; D013601:T-Lymphocytes / Q000166:cytology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism
C503684:CCNT1 protein, human; D056906:Cyclin T; D016213:Cyclins; D054322:tat Gene Products, Human Immunodeficiency Virus; D047389:Casein Kinase I; C447612:CDK11a protein, human; D018844:Cyclin-Dependent Kinases
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