Proteasomal Inhibition Potentiates Latent HIV Reactivation

Cary, Daniele C.; Peterlin, B. Matija

doi:10.1089/aid.2020.0040

Cited by 8 publications

(10 citation statements)

References 43 publications

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“…Levels of the CDK9 were largely unchanged in these cells (Figure 6D, panel 2, compare lane 2 to lane 1). Meanwhile, levels of CycT1 and CDK9 transcripts in W131AOTⅡ and OTⅡ cells remained unchanged (Figure 6E), which is consistent with previous observations that mRNA levels of CycT1 and CDK9 do not vary between resting and activated CD4+ T cells (Cary & Peterlin, 2020;Sung & Rice, 2006). Moreover, since these W131AOTII T cells exhibit impaired T cell receptor signaling (Nguyen et al, 2021), activating these cells with anti-CD3 and anti-CD28 antibodies did not increase levels of CycT1 (data not presented).…”

Section: Depletion Of Pkc Leads To Decreased Levels Of Cyct1 In Cellssupporting

confidence: 91%

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Reversible phosphorylation of cyclin T1 promotes assembly and stability of P-TEFb

Huang

Nguyen

Echeverria

et al. 2021

eLife

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The positive transcription elongation factor b (P-TEFb) is a critical coactivator for transcription of most cellular and viral genes, including those of HIV. While P-TEFb is regulated by 7SK snRNA in proliferating cells, P-TEFb is absent due to diminished levels of CycT1 in quiescent and terminally differentiated cells, which has remained unexplored. In these cells, we found that CycT1 not bound to CDK9 is rapidly degraded. Moreover, productive CycT1:CDK9 interactions are increased by PKC-mediated phosphorylation of CycT1 in human cells. Conversely, dephosphorylation of CycT1 by PP1 reverses this process. Thus, PKC inhibitors or removal of PKC by chronic activation results in P-TEFb disassembly and CycT1 degradation. This finding not only recapitulates P-TEFb depletion in resting CD4+ T cells but also in anergic T cells. Importantly, our studies reveal mechanisms of P-TEFb inactivation underlying T cell quiescence, anergy, and exhaustion as well as proviral latency and terminally differentiated cells.

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Section: Depletion Of Pkc Leads To Decreased Levels Of Cyct1 In Cellssupporting

confidence: 91%

“…We observed previously that levels of CycT1 increase significantly in resting CD4+ T cells with the addition of bortezomib (Cary & Peterlin, 2020). Nevertheless, interactions between CycT1 and CDK9 remain lower than in activated primary CD4+ T cells.…”

Section: Depletion Of Pkc Leads To Decreased Levels Of Cyct1 In Cellsmentioning

confidence: 66%

Reversible phosphorylation of cyclin T1 promotes assembly and stability of P-TEFb

Huang

Nguyen

Echeverria

et al. 2021

eLife

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“…cells remained unchanged (Fig. 6E), which is consistent with previous observations that mRNA levels of CycT1 and CDK9 do not vary between resting and activated CD4+ T cells (Cary & Peterlin, 2020;Sung & Rice, 2006).…”

Section: Depletion Of Pkc Leads To Decreased Levels Of Cyct1 In Cellssupporting

confidence: 92%

“…The other approach would be to identify the E3 ligase that is responsible for the degradation of the unphosphorylated CycT1 protein. To this end, bortezomib and other proteasomal inhibitors have been examined already for the reversal of HIV latency in resting CD4+ T cells (Cary & Peterlin, 2020;Li et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Assembly and levels of P-TEFb depend on reversible phosphorylation of cyclin T1

Huang

Nguyen

Echeverria

et al. 2021

Preprint

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The positive transcription elongation factor b (P-TEFb) is a critical co-activator for transcription of most cellular and viral genes, including those of HIV. While P-TEFb is regulated by 7SK snRNA in proliferating cells, it is absent in quiescent and terminally differentiated cells, which has remained unexplored. In these cells, we found that CycT1 not bound to CDK9 is rapidly degraded. Moreover, productive CycT1:CDK9 interactions require phosphorylation of two threonine residues (Thr143 and Thr149) in CycT1 by PKC. Conversely, PP1 dephosphorylates these sites. Thus, PKC inhibitors or removal of PKC by chronic activation results in P-TEFb disassembly and CycT1 degradation. This finding not only recapitulates P-TEFb depletion in resting CD4+ T cells but also in anergic T cells. Importantly, our studies reveal mechanisms of P-TEFb inactivation underlying T cell quiescence, anergy, and exhaustion as well as proviral latency and terminal differentiation of cells.

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“…This facilitates an efficient measurement of transcription rate. However, it also requires a special precaution for using 2D10 cell to study HIV latency particularly when protease inhibitors (PIs), including clinically approved bortezomib, are used as LRAs [ 116 , 117 ] since PIs can also stabilize EGFP proteins.…”

Section: 2d10mentioning

confidence: 99%

Experimental Systems for Measuring HIV Latency and Reactivation

Fujinaga

Cary

2020

Viruses

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The final obstacle to achieving a cure to HIV/AIDS is the presence of latent HIV reservoirs scattered throughout the body. Although antiretroviral therapy maintains plasma viral loads below the levels of detection, upon cessation of therapy, the latent reservoir immediately produces infectious progeny viruses. This results in elevated plasma viremia, which leads to clinical progression to AIDS. Thus, if a HIV cure is ever to become a reality, it will be necessary to target and eliminate the latent reservoir. To this end, tremendous effort has been dedicated to locate the viral reservoir, understand the mechanisms contributing to latency, find optimal methods to reactivate HIV, and specifically kill latently infected cells. Although we have not yet identified a therapeutic approach to completely eliminate HIV from patients, these efforts have provided many technological breakthroughs in understanding the underlying mechanisms that regulate HIV latency and reactivation in vitro. In this review, we summarize and compare experimental systems which are frequently used to study HIV latency. While none of these models are a perfect proxy for the complex systems at work in HIV+ patients, each aim to replicate HIV latency in vitro.

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Proteasomal Inhibition Potentiates Latent HIV Reactivation

Cited by 8 publications

References 43 publications

Reversible phosphorylation of cyclin T1 promotes assembly and stability of P-TEFb

Reversible phosphorylation of cyclin T1 promotes assembly and stability of P-TEFb

Assembly and levels of P-TEFb depend on reversible phosphorylation of cyclin T1

Experimental Systems for Measuring HIV Latency and Reactivation

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