Use of ATP analogs to inhibit HIV-1 transcription

Narayanan, Aarthi; Sampey, Gavin C.; Duyne, Rachel Van; Guendel, Irene; Kehn-Hall, Kylene; Roman, Jessica; Currer, Robert; Galons, Hervé; Oumata, Nassima; Joseph, Benoı̂t; Meijer, Laurent; Caputi, Massimo; Nekhai, Sergeï; Kashanchi, Fatah

doi:10.1016/j.virol.2012.06.007

Cited by 24 publications

(26 citation statements)

References 61 publications

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“…To characterize exosomal and viral fractions, we utilized chromatography fractionation of intracellular complexes from infected cell extracts. We have previously successfully used this method to identify novel P-TEFb complexes from HIV-1-infected cells (48). The total cell extracts from chronically HIV-1-infected J1.1 cells were separated on a sizeexclusion column (over 55 fractions) in the presence of 500 mM salt buffer, and each 5th fraction (from 10 to 55) was tested for the presence of HIV-1 RNA copies by qRT-PCR using primers specific for either TAR RNA or unspliced HIV-1 RNA.…”

Section: Hiv-1 Tar Rna Released From Infected Cells Both In Vitro Andmentioning

confidence: 99%

Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA

Sampey

Saifuddin

Schwab

et al. 2016

Journal of Biological Chemistry

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182

273

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HIV-1 infection results in a chronic illness because longterm highly active antiretroviral therapy can lower viral titers to an undetectable level. However, discontinuation of therapy rapidly increases virus burden. Moreover, patients under highly active antiretroviral therapy frequently develop various metabolic disorders, neurocognitive abnormalities, and cardiovascular diseases. We have previously shown that exosomes containing trans-activating response (TAR) element RNA enhance susceptibility of undifferentiated naive cells to HIV-1 infection. This study indicates that exosomes from HIV-1-infected primary cells are highly abundant with TAR RNA as detected by RT-real time PCR. Interestingly, up to a million copies of TAR RNA/l were also detected in the serum from HIV-1-infected humanized mice suggesting that TAR RNA may be stable in vivo. Incubation of exosomes from HIV-1-infected cells with primary macrophages resulted in a dramatic increase of proinflammatory cytokines, IL-6 and TNF-␤, indicating that exosomes containing TAR RNA could play a direct role in control of cytokine gene expression. The intact TAR molecule was able to bind to PKR and TLR3 effectively, whereas the 5 and 3 stems (TAR microRNAs) bound best to TLR7 and -8 and none to PKR. Binding of TAR to PKR did not result in its phosphorylation, and therefore, TAR may be a dominant negative decoy molecule in cells. The TLR binding through either TAR RNA or TAR microRNA potentially can activate the NF-B pathway and regulate cytokine expression. Collectively, these results imply that exosomes containing TAR RNA could directly affect the proinflammatory cytokine gene expression and may explain a possible mechanism of inflammation observed in HIV-1-infected patients under cART.

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Section: Hiv-1 Tar Rna Released From Infected Cells Both In Vitro Andmentioning

confidence: 99%

Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA

Sampey

Saifuddin

Schwab

et al. 2016

Journal of Biological Chemistry

Self Cite

182

273

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“…More recent findings, however, indicate that novel virus-and host-based inhibitors can inhibit HIV-1 transcription without affecting normal cellular functions. Such compounds include WP631, temacrazine, and various cyclin-dependent kinase (Cdk) inhibitors (69)(70)(71)(72)(73)(74)(75). In the last 10 years, host-based therapies have shed light on potential targets that had previously not been fully recognized.…”

mentioning

confidence: 99%

Novel Neuroprotective GSK-3β Inhibitor Restricts Tat-Mediated HIV-1 Replication

Guendel

Iordanskiy

Duyne

et al. 2014

J Virol

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“…The crystal structure of CDK9/cyclin T1/Tat complex has recently been resolved, revealing a main interaction between Tat and cyclin T1, but also with the T-loop of CDK9 (Gu et al 2014; Tahirov et al 2010). These studies suggested a conformational change in P-TEFb upon Tat binding, which opened the possibility to design inhibitors targeting specifically the interface of this viral protein/cellular host complex, without affecting Tat-free P-TEFb complexes, thereby avoiding toxicity (Narayanan et al 2012; Ramakrishnan et al 2012; Sedore et al 2007). …”

Section: Inhibition Of P-tefb An Essential Cellular Complex For Himentioning

confidence: 99%

“…The third generation of R-roscovitine, an ATP analogue named CR8#13 (Carpio et al 2010), inhibits Tat-activated transcription by targeting specifically CDK9 (Narayanan et al 2012). CR8#13 displays an IC 50 of 10 nM in TNF-α activated chronically infected OM-10.1 cells and inhibits RT activity by 90 % in PBMCs at 100 nM without displaying major toxicity.…”

Section: Inhibition Of P-tefb An Essential Cellular Complex For Himentioning

confidence: 99%

See 1 more Smart Citation

Targeting HIV Transcription: The Quest for a Functional Cure

Mousseau

Mediouni

Valente

2015

The Future of HIV-1 Therapeutics

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Antiretroviral therapy (ART) potently suppresses HIV-1 replication, but the virus persists in quiescent infected CD4+T cells as a latent integrated provirus, and patients must indefinitely remain on therapy. If ART is terminated, these integrated proviruses can reactivate, driving new rounds of infection. A functional cure for HIV requires eliminating low-level ongoing viral replication that persists in certain tissue sanctuaries and preventing viral reactivation. The HIV Tat protein plays an essential role in HIV transcription by recruiting the kinase activity of the P-TEFb complex to the viral mRNA’s stem–bulge–loop structure, TAR, activating transcriptional elongation. Because the Tat-mediated transactivation cascade is critical for robust HIV replication, the Tat/TAR/P-TEFb complex is one of the most attractive targets for drug development. Importantly, compounds that interfere with transcription could impair viral reactivation, low-level ongoing replication, and replenishment of the latent reservoir, thereby reducing the size of the latent reservoir pool. Here, we discuss the potential importance of transcriptional inhibitors in the treatment of latent HIV-1 disease and review recent findings on targeting Tat, TAR, and P-TEFb individually or as part of a complex. Finally, we discuss the impact of extracellular Tat in HIV-associated neurocognitive disorders and cancers.

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Use of ATP analogs to inhibit HIV-1 transcription

Cited by 24 publications

References 61 publications

Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA

Exosomes from HIV-1-infected Cells Stimulate Production of Pro-inflammatory Cytokines through Trans-activating Response (TAR) RNA

Novel Neuroprotective GSK-3β Inhibitor Restricts Tat-Mediated HIV-1 Replication

Targeting HIV Transcription: The Quest for a Functional Cure

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