Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0019693 (HIV)
 170,526 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cdk9 is a member of the Cdc2-like family of kinases. Its cyclin partners are members of the family of cyclin T (T1, T2a and T2b) and cyclin K. The Cdk9/cyclin T complexes appear to be involved in regulating several physiological processes. Cdk9/cyclin T1 belongs to the P-TEFb complex, and is responsible for the phosphorylation of the carboxyl-terminal domain (CTD) of the RNA Polymerase II, thus promoting general elongation. Cdk9 has also been described as the kinase of the TAK complex, which is homologous to the P-TEFb complex and involved in HIV replication. Cdk9 also appears to be involved in the differentiation program of several cell types, such as muscle cells, monocytes and neurons, suggesting that it may have a function in controlling specific differentiative pathways. In addition, Cdk9 seems to have an anti-apoptotic function in monocytes, that may be related to its control over differentiation of monocytes. This data suggests the involvement of Cdk9 in several physiological processes in the cell, the deregulation of which may be related to the genesis of transforming events, that may in turn lead to the onset of cancer. In addition, since the complex Cdk9/cyclin T1 is able to bind to the HIV-1 product Tat, the study of the functions of Cdk9/cyclin T may be of interest in understanding the basal mechanisms that regulate HIV replication.
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PMID:CDK9: from basal transcription to cancer and AIDS. 1243 43

The transcriptional elongation of human immunodeficiency virus type 1 (HIV-1) is mediated by the virally encoded transactivator Tat and its cellular cofactor, positive transcription elongation factor b (P-TEFb). The human cyclin T1 (hCycT1) subunit of P-TEFb forms a stable complex with Tat and the transactivation response element (TAR) RNA located at the 5' end of all viral transcripts. Previous studies have demonstrated that hCycT1 binds Tat in a Zn(2+)-dependent manner via the cysteine at position 261, which is a tyrosine in murine cyclin T1. In the present study, we mutated all other cysteines and histidines that could be involved in this Zn(2+)-dependent interaction. Because all of these mutant proteins except hCycT1(C261Y) activated viral transcription in murine cells, no other cysteine or histidine in hCycT1 is responsible for this interaction. Next, we fused the N-terminal 280 residues in hCycT1 with Tat. Not only the full-length chimera but also the mutant hCycT1 with an N-terminal deletion to position 249, which retained the Tat-TAR recognition motif, activated HIV-1 transcription in murine cells. This minimal hybrid mutant hCycT1-Tat protein bound TAR RNA as well as human and murine P-TEFb in vitro. We conclude that this minimal chimera not only reproduces the high-affinity binding among P-TEFb, Tat, and TAR but also will be invaluable for determining the three-dimensional structure of this RNA-protein complex.
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PMID:A minimal chimera of human cyclin T1 and tat binds TAR and activates human immunodeficiency virus transcription in murine cells. 1243 19

Human immunodeficiency virus type 1 (HIV-1) gene expression is regulated by both cellular transcription factors and Tat. The ability of Tat to stimulate transcriptional elongation is dependent on its binding to TAR RNA in conjunction with cyclin T1 and CDK9. A variety of other cellular factors that bind to the HIV-1 long terminal repeat, including NF-kappaB, SP1, LBP, and LEF, are also important in the control of HIV-1 gene expression. Although these factors have been demonstrated to regulate HIV-1 gene expression by both genetic and biochemical analysis, in most cases a direct in vivo demonstration of their role on HIV-1 replication has not been established. Recently, the efficacy of RNA interference in mammalian cells has been shown utilizing small interfering RNAs (siRNAs) to result in the specific degradation of host mRNAs and decreases the levels of their corresponding proteins. In this study, we addressed whether siRNAs directed against either HIV-1 tat or reverse transcriptase or the NF-kappaB p65 subunit could specifically decrease the levels of these proteins and thus alter HIV-1 replication. Our results demonstrate the specificity of siRNAs for decreasing the expression of these viral and cellular proteins and inhibiting HIV-1 replication. These studies suggest that RNA interference is useful in exploring the biological role of cellular and viral regulatory factors involved in the control of HIV-1 gene expression.
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PMID:RNA interference directed against viral and cellular targets inhibits human immunodeficiency Virus Type 1 replication. 1243 22

We have cloned and sequenced the chimpanzee (Pan troglodytes) cyclin T1 cDNA and performed functional HIV-1 Tat trans-activation studies. A unique codon deletion leading to a deleted asparagine residue in the N-terminal region of the first cyclin domain was discovered. This mutation does not significantly change the trans-activation of HIV-1, suggesting that Tat-Cyclin T1 mediated transcription is not a major barrier to HIV replication in the chimpanzee.
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PMID:A unique amino acid deletion in the chimpanzee Cyclin T1 does not affect Tat trans-activation of HIV. 1244 7

P-TEFb, cyclin T1 + CDK9, is needed for the expression of cellular promoters and primate lentiviral long terminal repeats (LTRs). Curiously, cellular and lentiviral promoters differ dramatically in the requirements for positive transcriptional elongation factor (P-TEF) b activity. Lentiviral LTRs, but not cellular promoters, need an RNA-associated P-TEFb/Tat/TAR (trans-activation-responsive) RNA ternary complex. Ternary complex defective murine cycT1 is apparently inactive for lentiviral transcription. Why P-TEFb requires Tat/TAR for LTRs but not for cellular promoters remains unknown. To explore this question, we sought to determine whether DNA targeting of murine and human cyclin T1 can reconstitute a Tat/TAR-independent activity to the HIV-1 LTR. In the absence of Tat and TAR, we found that both HuCycT1 and MuCycT1 can robustly activate the HIV-1 LTR. We further showed that Sp1 is necessary and sufficient for this DNA-targeted activity. Thus, like cellular promoters, HIV-1 LTR can use P-TEFb function without a Tat/TAR RNA complex. This activity could explain recent findings of robust HIV-1 replication in rat cells that cannot form a P-TEFb/Tat/TAR moiety.
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PMID:Tat and trans-activation-responsive (TAR) RNA-independent induction of HIV-1 long terminal repeat by human and murine cyclin T1 requires Sp1. 1245 22

The HIV-1 transactivator protein, Tat, is an atypical transcriptional activator that functions through binding, not to DNA, but to a short leader RNA, TAR. Although details of its functional mechanism are still unknown, emerging findings suggest that Tat serves primarily to adapt co-activator complexes such as p300, PCAF and P-TEFb to the HIV-1 long terminal repeat. Hence, an understanding of how Tat interacts with these cofactors is crucial. It has recently been shown that acetylation at a single lysine, residue 50, regulated the association of Tat with PCAF. Here, we report that in the absence of Tat acetylation, PCAF binds to amino acids 20-40 within Tat. Interestingly, acetylation of Tat at Lys28 abrogates Tat-PCAF interaction. Acetylation at Lys50 creates a new site for binding to PCAF and dictates the formation of a ternary complex of Tat-PCAF-P-TEFb. Thus, differential lysine acetylation of Tat coordinates the interactions with its co-activators, cyclin T1 and PCAF. Our results may help in understanding the ordered recruitment of Tat co-activators to the HIV-1 promoter.
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PMID:Differential acetylation of Tat coordinates its interaction with the co-activators cyclin T1 and PCAF. 1248 2

We examine the potential for a broad range of small animal cells, including rodent, mink, and avian cells, from multiple tissues to support postintegration steps of HIV-1 replication. These cells were engineered so as to support a stable expression of human cyclin T1 and were further transduced with HIV-1 gag and pol genes. Viral gene expression was activated by the presence of human cyclin T1, but, with the exception of mink cells, was not at the level seen in human cells. Furthermore, there were considerable defects in p24 CA release, in particular in the case of rodent cells. Fractionation of Gag proteins by sucrose floatation revealed that the Gag in human cells trafficked to membrane fractions and was processed to p24 CA and p17 MA efficiently. Confocal imaging demonstrated that Gag was localized in a punctate pattern at the plasma membrane as well as intracellular membrane trans-Golgi cisternae in these cells. In contrast, the majority of Gag in rodent cells was largely present in cytosolic complexes and remained unprocessed. Labeling with [9,10(n)-(3)H]myristic acid showed a similar degree of N-myristoylated Pr55(gag) in rodent and human cells, indicating that while N-myristoylation of Gag was essential for membrane binding, it was not sufficient to confer membrane targeting specificity. Remarkably, despite the reduced level of intracellular Gag processing, mink Mv.1.Lu cells did not appear to differ significantly from human cells in support of virion assembly and release. Analysis of reciprocal heterokaryons suggested that the cellular factor(s) required for efficient assembly and release of infectious virions is lacking in murine cells but appears to be functionally present in mink as well as human cells. Our findings confirm and extend previous reports of multiple blocks to HIV replication in nonhuman cells that are most profound in murine cells. They also raise the possibility that other small animals, such as mink, could serve as novel model systems for studying HIV-1 infection and disease.
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PMID:Ability of small animal cells to support the postintegration phase of human immunodeficiency virus type-1 replication. 1250 51

Cyclin T1, together with the kinase CDK9, is a component of the transcription elongation factor P-TEFb which binds the human immunodeficiency virus type 1 (HIV-1) transactivator Tat. P-TEFb facilitates transcription by phosphorylating the carboxy-terminal domain (CTD) of RNA polymerase II. Cyclin T1 is an exceptionally large cyclin and is therefore a candidate for interactions with regulatory proteins. We identified granulin as a cyclin T1-interacting protein that represses expression from the HIV-1 promoter in transfected cells. The granulins, mitogenic growth factors containing repeats of a cysteine-rich motif, were reported previously to interact with Tat. We show that granulin formed stable complexes in vivo and in vitro with cyclin T1 and Tat. Granulin bound to the histidine-rich domain of cyclin T1, which was recently found to bind to the CTD, but not to cyclin T2. Binding of granulin to P-TEFb inhibited the phosphorylation of a CTD peptide. Granulin expression inhibited Tat transactivation, and tethering experiments showed that this effect was due, at least in part, to a direct action on cyclin T1 in the absence of Tat. In addition, granulin was a substrate for CDK9 but not for the other transcription-related kinases CDK7 and CDK8. Thus, granulin is a cellular protein that interacts with cyclin T1 to inhibit transcription.
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PMID:The growth factor granulin interacts with cyclin T1 and modulates P-TEFb-dependent transcription. 1258 88

In vivo studies for understanding viral transmission and replication, host immune responses, and pathogenesis of human immunodeficiency virus type 1 (HIV-1) infection would greatly benefit from the establishment of a small-animal model. In this study, we explored the potential of American mink (Mustera vison) as a susceptible host. We found that primary cells and cell lines derived from this species efficiently supported trans-activation of the HIV-1 long terminal repeat by Tat. Accordingly, the cysteine residue at position 261, which has been shown to be important for interaction of the human cyclin T1 with the HIV-1 regulatory protein Tat, is conserved in the mink homologue. No species-specific defect in Rev function could be detected in mink cells. In addition, primary splenocytes, fibroblasts, and the Mv.1.Lu cell line from American mink supported early as well as late HIV-1 gene expression following infection with vesicular stomatitis G protein-pseudotyped HIV-1 viruses, at levels comparable to those seen with permissive human cells. Furthermore, the mink Mv.1.Lu cell line stably expressing human CD4 and CCR5 receptors supported a spreading HIV-1 infection with few, if any, deficiencies compared to findings in human cell lines. This indicates the potential of HIV-1 to replicate in these cells once the blockade at the stage of virus entry has been removed. These results clearly show that cells from American mink generally pose no functional intracellular block to HIV-1 replication, and collectively they raise the possibility that this animal species could be engineered to support HIV-1 infection, providing a useful small-animal model for evaluating de novo infection by HIV-1.
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PMID:Susceptibility of mink (Mustera vision)-derived cells to replication by human immunodeficiency virus type 1. 1269 13

Human cyclin T1, the cyclin partner of Cdk9 kinase in the positive transcription elongation factor b (P-TEFb), is an essential cellular cofactor that is recruited by the human immunodeficiency virus type 1 (HIV-1) Tat transactivator to promote transcriptional elongation from the HIV-1 long terminal repeat (LTR). Here we exploit fluorescence resonance energy transfer (FRET) to demonstrate that cyclin T1 physically interacts in vivo with the promyelocytic leukaemia (PML) protein within specific subnuclear compartments that are coincident with PML nuclear bodies. Deletion mutants at the C-terminal region of cyclin T1 are negative for FRET with PML and fail to localize to nuclear bodies. Cyclin T1 and PML are also found associated outside of nuclear bodies, and both proteins are present at the chromatinized HIV-1 LTR promoter upon Tat transactivation. Taken together these results suggest that PML proteins regulate Tat- mediated transcriptional activation by modulating the availability of cyclin T1 and other essential cofactors to the transcription machinery.
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PMID:Recruitment of human cyclin T1 to nuclear bodies through direct interaction with the PML protein. 1272 82


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