Regulation of HIV‐1 transcription at 3% versus 21% oxygen concentration

Charles, Sharroya; Ammosova, Tatyana; Cardenas, Jessica C.; Foster, Altreisha; Rotimi, Jamie; Jerebtsova, Marina; Ayodeji, Abisola A.; Niu, Xiaomei; Ray, Patricio E.; Gordeuk, Victor R.; Kashanchi, Fatah; Nekhai, Sergeï

doi:10.1002/jcp.21882

Cited by 28 publications

(37 citation statements)

References 63 publications

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“…We have previously shown that hypoxia decreases the expression of IB-␣ but not that of Gro-␤ or HLA-DRA (48). Data presented in this report suggest that inhibition of CDK9-depedent genes by PPY-based iron chelators could lead to the overexpression of IB-␣ but have no effect on HLA expression.…”

Section: Discussionmentioning

confidence: 57%

Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase IκB-α Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription

Kumari

Iordanskiy

Kovalskyy

et al. 2014

Antimicrob Agents Chemother

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dHIV-1 transcription is activated by the Tat protein, which recruits CDK9/cyclin T1 to the HIV-1 promoter. CDK9 is phosphorylated by CDK2, which facilitates formation of the high-molecular-weight positive transcription elongation factor b (P-TEFb) complex. We previously showed that chelation of intracellular iron inhibits CDK2 and CDK9 activities and suppresses HIV-1 transcription, but the mechanism of the inhibition was not understood. In the present study, we tested a set of novel iron chelators for the ability to inhibit HIV-1 transcription and elucidated their mechanism of action. Novel phenyl-1-pyridin-2yl-ethanone (

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Section: Discussionmentioning

confidence: 57%

Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase IκB-α Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription

Kumari

Iordanskiy

Kovalskyy

et al. 2014

Antimicrob Agents Chemother

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“…The chelators also signifi cantly reduced association of CDK9 with cyclin T1 and reduced phosphorylation of Ser-2 residues of RNA polymerase II C-terminal domain [ 9 ] , suggesting that the mechanism of inhibition includes deregulation of CDK2 and CDK9. HIV-1 transcription was inhibited in the cells cultured at 3% O 2 compared to 21% O 2 [ 14 ] . At 3% O 2 , the activity of CDK9/cyclin T1 was inhibited and Sp1 activity was reduced, whereas the activity of other host cell factors including CDK2 and NF-κ B was not affected [ 14 ] .…”

Section: Cellular Iron and Hypoxia Infl Uence Hiv-1 Transcriptionmentioning

confidence: 87%

“…HIV-1 transcription was inhibited in the cells cultured at 3% O 2 compared to 21% O 2 [ 14 ] . At 3% O 2 , the activity of CDK9/cyclin T1 was inhibited and Sp1 activity was reduced, whereas the activity of other host cell factors including CDK2 and NF-κ B was not affected [ 14 ] .…”

Section: Cellular Iron and Hypoxia Infl Uence Hiv-1 Transcriptionmentioning

confidence: 87%

“…But more recent studies showed that hypoxia-induced p27 protein expression was abrogated by RNAi-mediated knockdown of HIF-1a [ 13 ] suggesting that HIF-1a might be critical for the induction of p27. In our recent study, we found that the activity of Cdk9 (see more details in HIV section) is inhibited when cells are cultured at 3% oxygen [ 14 ] , or treated with iron chelators [ 9 ] . Because Cdk9 regulates most if not all RNA polymerase II-mediated transcription [ 15 ] , iron chelation is likely to have a general transcription inhibitory effect.…”

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confidence: 98%

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Iron Metabolism in Cancer and Infection

Nekhai

2011

Iron Physiology and Pathophysiology in Humans

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Progression through the G1, S, G2, and M phases of the cell cycle is regulated by sets of Cdks bound to corresponding cyclins (reviewed in [ 1 ] ). Transition through the G1 phase is regulated by Cdk4/ cyclin D1 and by Cdk6/cyclin D3. Cdk2/cyclin E is active at the late G1 phase and is responsible for the G1/S transition. Progression through the S phase is regulated by Cdk2/cyclin A. DNA synthesis during the S phase critically relies on the enzymatic activity of ribonucleotide reductase [ 2 ] . The S/ G2 transition is regulated by Cdk1/cyclin A. Cdk1/cyclin B is responsible for the G2/M transition and for the completion of mitosis. Ribonucleotide ReductaseRibonucleotide reductase, the rate limiting enzyme for DNA synthesis and therefore critical for the S phase of the cell cycle, is composed of two subunits [ 2 ] . The R1 subunit of ribonucleotide reductase binds substrate and the R2 subunit contains nonheme iron which is important for enzymatic activity [ 2 ] . Inhibition of the enzymatic activity of R2 by iron chelators 311 and desferrioxamine inhibited growth of a number of cancer cell lines [ 3 ] . Recent studies have suggested that iron depletion infl uences the control of the cell cycle and angiogenesis and may suppress metastasis [ 4 ] .

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“…There is also growing evidence that hypoxia and HIF affect the host-virus interaction and hence the pathogenesis of the viruses that either posses a DNA genome or pass through a DNA stage, contain hypoxia-responsive elements in their promoters, and need the nucleus for their replication. For example, hypoxia enhances gene expression of human B19 erythrovirus (9,29) and replication of oncolytic herpes simplex virus (1) and induces lytic replication of Epstein-Barr virus (18,41) and Kaposi sarcoma-associated herpesvirus (KSHV) (12,15), but it suppresses replication of the oncolytic parvovirus minute virus of mice (35), adenovirus (36), Moloney murine leukemia virus (M-MuLV) (30), and HIV-1 (11,41).…”

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confidence: 99%

Hypoxia Induces the Gene Expression and Extracellular Transmission of Persistent Lymphocytic Choriomeningitis Virus

Tomaskova

Ovečková

Labudová

et al. 2011

J Virol

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The physiological context of virus-infected cells can markedly affect multiplication and spread of the virus progeny. During persistent infection, the virus exploits the host cell without disturbing its vital functions. However, microenvironmental hypoxia can uncouple this intimate relationship and escalate virus pathogenesis. Accumulating evidence suggests that hypoxia-inducible factor (HIF) modulates gene expression of the viruses that pass through a DNA stage, contain hypoxia-responsive promoter elements, and replicate in the nucleus. Here we show that hypoxia can influence the gene expression and transmission of the cytoplasmic RNA virus lymphocytic choriomeningitis virus (LCMV), which is a neglected human pathogen and teratogen. The MX strain of LCMV, which we used as a model, replicates in a persistent mode in human HeLa cells, fails to produce mature envelope glycoproteins, and spreads through cell-cell contacts in the absence of extracellular infectious virions. Both exposure of MX-infected HeLa cells to chronic hypoxia and gene transfer approaches led to increased virus RNA transcription and higher levels of the viral proteins via a HIFdependent mechanism. Moreover, hypoxia enhanced the formation of infectious virions capable of transmitting LCMV by cell-free medium. This LCMV "reactivation" might have health-compromising consequences in hypoxia-associated situations, such as fetal development and ischemia-related pathologies.The prototypic arenavirus lymphocytic choriomeningitis virus (LCMV) provides an important model for investigations of the mechanisms of viral persistence and pathogenesis. Studies using this model led to major advances in virology and immunology that apply universally to other viral and microbial infections of humans (5,7,43,45). Even though LCMV infections are mostly asymptomatic and often remain unnoticed, compelling evidence indicates that LCMV is a neglected human pathogen of clinical significance, especially in cases of congenital infections leading to an increased risk of spontaneous abortion or central nervous system (CNS) disorders and chorioretinitis (3,4,17,44). Moreover, LCMV poses a special threat to immunocompromised individuals, as tragically illustrated by recent cases of transplant-associated infections by LCMV with fatal outcomes in the United States (13) and Australia (25). LCMV has a bisegmented single-stranded RNA genome and a life cycle confined to the cell cytoplasm. The genome consists of a small segment (S) (3.4 kb) and a large segment (L) (7.2 kb). Each genomic segment uses an ambisense coding strategy to direct the synthesis of two polypeptides from two opposite open reading frames separated by an intergenic region. The S segment encodes a major viral protein nucleoprotein (NP) and a glycoprotein precursor (GPC), which is posttranslationally cleaved into peripheral glycoprotein 1 (GP1) and transmembrane glycoprotein 2 (GP2). The L segment encodes a viral RNA-dependent RNA polymerase (L) and a small regulatory RING domain-containing Z protein (Z) (6, 42). S...

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Regulation of HIV‐1 transcription at 3% versus 21% oxygen concentration

Cited by 28 publications

References 63 publications

Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase IκB-α Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription

Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase IκB-α Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription

Iron Metabolism in Cancer and Infection

Hypoxia Induces the Gene Expression and Extracellular Transmission of Persistent Lymphocytic Choriomeningitis Virus

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