Hypoxia Inhibits HIV-1 Transcription.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1305-1305
Author(s):  
Sergei Nekhai ◽  
Charles Sharroya ◽  
Tatyana Ammosova ◽  
Xiaomei Nui ◽  
Marina Jerebtsova ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Oxygen Tension ◽  
Protein Phosphatase ◽  
Tissue Oxygenation ◽  
Protein Phosphatase 1 ◽  
Tat Protein ◽  
Cyclin T1 ◽  
Hiv Transcription ◽  
Hiv 1

Abstract The hypoxic response is an important component of the body’s reaction to impaired tissue oxygenation associated with the anemia and vasoocclusive episodes of sickle cell disease (SCD). It has been reported that HIV infection progresses relatively slowly in patients with SCD (Am J Hematol1998;59:199–207). HIV-1 Tat protein promotes transcription of HIV-1 genes by inducing CDK9/cyclin T1 to phosphorylate the C-terminal domain of RNA polymerase-II. Our previous studies indicate that protein phosphatase-1 (PP1) promotes Tat-induced HIV-1 transcription (J Biol Chem2003;278:32189–941), apparently by interacting with HIV-1 Tat, for disruption of this interaction prevents induction of transcription (J Biol Chem2005;280:36364–71). Recently PP1 activity was shown to be decreased in hypoxia in part through increased association of PP1 with NIPP1 (J Cell Physiol 2006 Jul 6; Epub ahead of print). We hypothesized that decreased PP1 activity during hypoxia would reduce HIV-1 transcription and viral replication, and we have obtained experimental results consistent with this hypothesis.Increased expression of nuclear inhibitor of PP1 (NIPP1) was associated with inhibition of HIV-1 transcription and viral replication.Low oxygen tension (3%–6% O2) was associated with transient inhibition of HIV-1 transcription in transfected 293T and HeLa cells.Low oxygen tension was associated with inhibition of HIV-1 transcription in CEM T cells infected with pseudotyped HIV-1 virus. We are now planning to examine the possible role of altered PP1 activity in the observed inhibition of HIV-1 transcription during hypoxia. Thus, a clinical insight from patients with SCD has pointed the way to investigating the influence of hypoxia on HIV transcription. An improved understanding of how oxygen status influences viral activation versus inactivation might open new possibilities for treatment of hidden HIV-1 reservoirs that harbor non-replicating HIV-1 virus.

scholarly journals Nuclear Targeting of Protein Phosphatase-1 by HIV-1 Tat Protein

2005 ◽  
Vol 280 (43) ◽  
pp. 36364-36371 ◽  
Author(s):  
Tatyana Ammosova ◽  
Marina Jerebtsova ◽  
Monique Beullens ◽  
Bart Lesage ◽  
Angela Jackson ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Rna Polymerase ◽  
Rna Polymerase Ii ◽  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Tat Protein ◽  
Nuclear Targeting ◽  
Cyclin T1 ◽  
Immunodeficiency Virus ◽  
Hiv 1

Transcription of human immunodeficiency virus (HIV)-1 genes is activated by HIV-1 Tat protein, which induces phosphorylation of the C-terminal domain of RNA polymerase-II by CDK9/cyclin T1. We previously showed that Tat-induced HIV-1 transcription is regulated by protein phosphatase-1 (PP1). In the present study we demonstrate that Tat interacts with PP1 and that disruption of this interaction prevents induction of HIV-1 transcription. We show that PP1 interacts with Tat in part through the binding of Val36 and Phe38 of Tat to PP1 and that Tat is involved in the nuclear and subnuclear targeting of PP1. The PP1 binding mutant Tat-V36A/F38A displayed a decreased affinity for PP1 and was a poor activator of HIV-1 transcription. Surprisingly, Tat-Q35R mutant that had a higher affinity for PP1 was also a poor activator of HIV-1 transcription, because strong PP1 binding competed out binding of Tat to CDK9/cyclin T1. Our results suggest that Tat might function as a nuclear regulator of PP1 and that interaction of Tat with PP1 is critical for activation of HIV-1 transcription by Tat.

scholarly journals Induction of TAK (Cyclin T1/P-TEFb) in Purified Resting CD4+ T Lymphocytes by Combination of Cytokines

2001 ◽  
Vol 75 (23) ◽  
pp. 11336-11343 ◽  
Author(s):  
Romi Ghose ◽  
Li-Ying Liou ◽  
Christine H. Herrmann ◽  
Andrew P. Rice
Keyword(s):  
T Lymphocytes ◽  
Rna Polymerase Ii ◽  
Interleukin 2 ◽  
Cellular Protein ◽  
Peripheral Blood Lymphocytes ◽  
Tat Protein ◽  
Necrosis Factor Alpha ◽  
Cyclin T1 ◽  
Protein Levels ◽  
Hiv 1

ABSTRACT Combinations of cytokines are known to reactivate transcription and replication of latent human immunodeficiency virus type 1 (HIV-1) proviruses in resting CD4+ T lymphocytes isolated from infected individuals. Transcription of the HIV-1 provirus by RNA polymerase II is strongly stimulated by the viral Tat protein. Tat function is mediated by a cellular protein kinase known as TAK (cyclin T1/P-TEFb) that is composed of Cdk9 and cyclin T1. We have found that treatment of peripheral blood lymphocytes and purified resting CD4+ T lymphocytes with the combination of interleukin-2 (IL-2), IL-6, and tumor necrosis factor alpha resulted in an increase in Cdk9 and cyclin T1 protein levels and an increase in TAK enzymatic activity. The cytokine induction of TAK in resting CD4+ T lymphocytes did not appear to require proliferation of lymphocytes. These results suggest that induction of TAK by cytokines secreted in the microenvironment of lymphoid tissue may be involved in the reactivation of HIV-1 in CD4+ T lymphocytes harboring a latent provirus.

scholarly journals The AFF4 scaffold binds human P-TEFb adjacent to HIV Tat

eLife ◽  
2013 ◽  
Vol 2 ◽  
Author(s):  
Ursula Schulze-Gahmen ◽  
Heather Upton ◽  
Andrew Birnberg ◽  
Katherine Bao ◽  
Seemay Chou ◽  
...  
Keyword(s):  
Rna Polymerase Ii ◽  
Elongation Factor ◽  
Regulatory Proteins ◽  
Tat Protein ◽  
Elongation Complex ◽  
Cyclin T1 ◽  
Subunit Interface ◽  
Hiv Tat ◽  
Gene Transcripts ◽  
Hiv 1

Human positive transcription elongation factor b (P-TEFb) phosphorylates RNA polymerase II and regulatory proteins to trigger elongation of many gene transcripts. The HIV-1 Tat protein selectively recruits P-TEFb as part of a super elongation complex (SEC) organized on a flexible AFF1 or AFF4 scaffold. To understand this specificity and determine if scaffold binding alters P-TEFb conformation, we determined the structure of a tripartite complex containing the recognition regions of P-TEFb and AFF4. AFF4 meanders over the surface of the P-TEFb cyclin T1 (CycT1) subunit but makes no stable contacts with the CDK9 kinase subunit. Interface mutations reduced CycT1 binding and AFF4-dependent transcription. AFF4 is positioned to make unexpected direct contacts with HIV Tat, and Tat enhances P-TEFb affinity for AFF4. These studies define the mechanism of scaffold recognition by P-TEFb and reveal an unanticipated intersubunit pocket on the AFF4 SEC that potentially represents a target for therapeutic intervention against HIV/AIDS.

scholarly journals Regulation of CDK9 Activity by Phosphorylation and Dephosphorylation

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Sergei Nekhai ◽  
Michael Petukhov ◽  
Denitra Breuer
Keyword(s):  
Cell Cycle ◽  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Comprehensive Review ◽  
Cyclin T1 ◽  
Typical Cell ◽  
Cdk9 Phosphorylation ◽  
Protein Components ◽  
Cycle Dependent ◽  
Hiv 1

HIV-1 transcription is regulated by CDK9/cyclin T1, which, unlike a typical cell cycle-dependent kinase, is regulated by associating with 7SK small nuclear ribonuclear protein complex (snRNP). While the protein components of this complex are well studied, the mechanism of the complex formation is still not fully understood. The association of CDK9/cyclin T1 with 7SK snRNP is, in part, regulated by a reversible CDK9 phosphorylation. Here, we present a comprehensive review of the kinases and phosphatases involved in CDK9 phosphorylation and discuss their role in regulation of HIV-1 replication and potential for being targeted for drug development. We propose a novel pathway of HIV-1 transcription regulation via CDK9 Ser-90 phosphorylation by CDK2 and CDK9 Ser-175 dephosphorylation by protein phosphatase-1.

Novel role of the protein phosphatase 1 regulatory subunit PPP1R3A in atrial fibrillation

2018 ◽  
Vol 124 ◽  
pp. 108
Author(s):  
Katherina Alsina ◽  
Mohit Hulsurkar ◽  
Chunxia Yao ◽  
Barbara Langer ◽  
David Chiang ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Protein Phosphatase ◽  
Protein Phosphatase 1 ◽  
Regulatory Subunit

scholarly journals Ref2, a regulatory subunit of the yeast protein phosphatase 1, is a novel component of cation homoeostasis

2010 ◽  
Vol 426 (3) ◽  
pp. 355-364 ◽  
Author(s):  
Jofre Ferrer-Dalmau ◽  
Asier González ◽  
Maria Platara ◽  
Clara Navarrete ◽  
José L. Martínez ◽  
...  
Keyword(s):  
Protein Phosphatase ◽  
Living Organism ◽  
Calcium Sensitivity ◽  
Growth Conditions ◽  
Protein Phosphatase 1 ◽  
Regulatory Subunit ◽  
Alkaline Ph ◽  
Yeast Protein ◽  
Increased Sensitivity

Maintenance of cation homoeostasis is a key process for any living organism. Specific mutations in Glc7, the essential catalytic subunit of yeast protein phosphatase 1, result in salt and alkaline pH sensitivity, suggesting a role for this protein in cation homoeostasis. We screened a collection of Glc7 regulatory subunit mutants for altered tolerance to diverse cations (sodium, lithium and calcium) and alkaline pH. Among 18 candidates, only deletion of REF2 (RNA end formation 2) yielded increased sensitivity to these conditions, as well as to diverse organic toxic cations. The Ref2F374A mutation, which renders it unable to bind Glc7, did not rescue the salt-related phenotypes of the ref2 strain, suggesting that Ref2 function in cation homoeostasis is mediated by Glc7. The ref2 deletion mutant displays a marked decrease in lithium efflux, which can be explained by the inability of these cells to fully induce the Na+-ATPase ENA1 gene. The effect of lack of Ref2 is additive to that of blockage of the calcineurin pathway and might disrupt multiple mechanisms controlling ENA1 expression. ref2 cells display a striking defect in vacuolar morphogenesis, which probably accounts for the increased calcium levels observed under standard growth conditions and the strong calcium sensitivity of this mutant. Remarkably, the evidence collected indicates that the role of Ref2 in cation homoeostasis may be unrelated to its previously identified function in the formation of mRNA via the APT (for associated with Pta1) complex.

scholarly journals Functional Differences between Human and Bovine Immunodeficiency Virus Tat Transcription Factors

2000 ◽  
Vol 74 (10) ◽  
pp. 4666-4671 ◽  
Author(s):  
Hal P. Bogerd ◽  
Heather L. Wiegand ◽  
Paul D. Bieniasz ◽  
Bryan R. Cullen
Keyword(s):  
Cooperative Interaction ◽  
Bovine Immunodeficiency Virus ◽  
Viral Gene ◽  
Tat Protein ◽  
Cyclin T1 ◽  
Immunodeficiency Virus ◽  
Cellular Cofactor ◽  
Ltr Promoter ◽  
Hiv 1

ABSTRACT Transcriptional transactivation of the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR) promoter element by the essential viral Tat protein requires recruitment of positive transcription elongation factor b (P-TEFb) to the viral TAR RNA target. The recruitment of P-TEFb, which has been proposed to be necessary and sufficient for activation of viral gene expression, is mediated by the highly cooperative interaction of Tat and cyclin T1, an essential component of P-TEFb, with the HIV-1 TAR element. Species, such as rodents, that encode cyclin T1 variants that are unable to support TAR binding by the Tat-cyclin T1 heterodimer are also unable to support HIV-1 Tat function. In contrast, we here demonstrate that the bovine immunodeficiency virus (BIV) Tat protein is fully able to bind to BIV TAR both in vivo and in vitro in the absence of any cellular cofactor. Nevertheless, BIV Tat can specifically recruit cyclin T1 to the BIV TAR element, and this recruitment is as essential for BIV Tat function as it is for HIV-1 Tat activity. However, because the cyclin T1 protein does not contribute to TAR binding, BIV Tat is able to function effectively in cells from several species that do not support HIV-1 Tat function. Thus, BIV Tat, while apparently dependent on the same cellular cofactor as the Tat proteins encoded by other lentiviruses, is nevertheless unique in terms of the mechanism used to recruit the BIV Tat-cyclin T1 complex to the viral LTR promoter.

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