Human Immunodeficiency Virus Reactivation by Phorbol Esters or T-Cell Receptor Ligation Requires both PKCα and PKCθ

Trushin, Sergey; Bren, Gary D.; Asin, Susana; Pennington, Kevin N.; Payá, Carlos V.; Badley, Andrew D.

doi:10.1128/jvi.79.15.9821-9830.2005

Cited by 49 publications

(47 citation statements)

References 62 publications

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“…A similar CD28RE has been identified in the HIV-1 LTR, and accordingly, CD3/ CD28 signal integration is also required for optimal activation of the HIV-1 LTR (67, 68). Trushin et al previously demonstrated that PKC is a central integrative factor for both phorbol ester and TCR/CD28-mediated HIV-1 reactivation in a T cell line (J1.1 cells) (69). NF-B and AP-1 have been identified as the primary targets of PKC, and selective inhibition of certain AP-1 factors by AS601245 could thus differentially influence HIV-1 and cytokine gene expression, in particular, as a functional disparity between cytokine CD28RE and the HIV-1 LTR CD28RE has been described (17).…”

Section: Discussionmentioning

confidence: 99%

Kinase Control Prevents HIV-1 Reactivation in Spite of High Levels of Induced NF-κB Activity

Wolschendorf

Bosque

Shishido

et al. 2012

J Virol

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Despite its clinical importance, the molecular biology of HIV-1 latency control is at best partially understood, and the literature remains conflicting. The most recent description that latent HIV-1 is integrated into actively expressed host genes has further confounded the situation. This lack of molecular understanding complicates our efforts to identify therapeutic compounds or strategies that could reactivate latent HIV-1 infection in patients, a prerequisite for the eradication of HIV-1 infection. Currently, many therapeutic development efforts operate under the assumption that a restrictive histone code could govern latent infection and that either dissipation of the histone-based restrictions or NF-B activation could be sufficient to trigger HIV-1 reactivation. We here present data that suggest an additional, higher level of molecular control. During a high-content drug screening effort, we identified AS601245 as a potent inhibitor of HIV-1 reactivation in latently infected primary T cells and T cell lines. In either system, AS601245 inhibited HIV-1 reactivation despite high levels of induced NF-B activation. This finding suggests the presence of a gatekeeper kinase activity that controls latent HIV-1 infection even in the presence of high levels of NF-B activity. Potential therapeutic stimuli that do not target this gatekeeper kinase will likely fail to trigger efficient system-wide HIV-1 reactivation.

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Section: Discussionmentioning

confidence: 99%

Kinase Control Prevents HIV-1 Reactivation in Spite of High Levels of Induced NF-κB Activity

Wolschendorf

Bosque

Shishido

et al. 2012

J Virol

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“…PKCa is proposed to act in concert and/or in alternative pathways with PKCh to regulate the IkB/NFkB axis (Trushin et al, 2003); it has additional functions including HIV reactivation (Trushin et al, 2005), TCR downregulation (von Essen et al, 2006) and granule exocytosis (Grybko et al, 2007). PKCa-deficient mice have a severe defect in the Th1 response and IFNc secretion (Pfeifhofer et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

Transient PKCα shuttling to the immunological synapse is governed by (DGK)ζ and regulates L-selectin shedding

Gharbi

Ávila-Flores

Soutar

et al. 2013

Journal of Cell Science

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SummaryConsiderable evidence indicates that diacylglycerol (DAG) generation at the immunological synapse (IS) determines T cell functions by regulating the duration and amplitude of Ras/ERK signals. The exact mechanism by which DAG regulates Ras/ERK activation downstream of the T cell receptor (TCR) nonetheless remains poorly understood. Here we characterize PKCa as a previously unrecognized component of the machinery that translates cell receptor occupancy into Ras/ERK-propagated signals. We show transient translocation of PKCa to the IS, mediated by DAG generation at the contact area. Diacylglycerol kinase (DGK)f negatively regulated PKCa translocation kinetics, whereas PKCa activity limited its own persistence at the IS. Coordinated activation of DGKf and PKCa in response to antigen recognition regulated the amplitude and duration of Ras/ERK activation; this in turn mediated early processes of T cell surface proteolysis such as L-selectin shedding. Analysis of DGKf-deficient mice further showed that increased DAG signaling is translated to downstream elements of this pathway, as reflected by enhanced PKCa-dependent L-selectin shedding. We propose that early activation of a DAG-PKCa axis contributes to the mechanisms by which antigen affinity translates into TCR biological responses.

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“…In acutely infected cells, prostratin enhances cell survival possibly due to cytostatic effects (18). Most importantly, in latently infected cells, prostratin stimulates viral replication putatively through PKC-mediated phosphorylation of IκB kinase, which enables release and penetration of the transcription factor NF-κB into the cell nucleus (26), where its binding to the HIV LTR leads to viral gene expression and subsequent replication of the virus.…”

mentioning

confidence: 99%

Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo

Beans

Fournogerakis

Gauntlett

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

138

107

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Highly active antiretroviral therapy (HAART) decreases plasma viremia below the limits of detection in the majority of HIV-infected individuals, thus serving to slow disease progression. However, HAART targets only actively replicating virus and is unable to eliminate latently infected, resting CD4 + T cells. Such infected cells are potentially capable of reinitiating virus replication upon cessation of HAART, thus leading to viral rebound. Agents that would eliminate these reservoirs, when used in combination with HAART, could thus provide a strategy for the eradication of HIV. Prostratin is a preclinical candidate that induces HIV expression from latently infected CD4 + T cells, potentially leading to their elimination through a virus-induced cytopathic effect or host anti-HIV immunity. Here, we report the synthesis of a series of designed prostratin analogs and report in vitro and ex vivo studies of their activity relevant to induction of HIV expression. Members of this series are up to 100-fold more potent than the preclinical lead (prostratin) in binding to cell-free PKC, and in inducing HIV expression in a latently infected cell line and prostratin-like modulation of cell surface receptor expression in primary cells from HIV-negative donors. Significantly, selected members were also tested for HIV induction in resting CD4 + T cells isolated from infected individuals receiving HAART and were found to exhibit potent induction activity. These more potent agents and by extension related tunable analogs now accessible through the studies described herein should facilitate research and preclinical advancement of this strategy for HIV/AIDS eradication.

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Human Immunodeficiency Virus Reactivation by Phorbol Esters or T-Cell Receptor Ligation Requires both PKCα and PKCθ

Cited by 49 publications

References 62 publications

Kinase Control Prevents HIV-1 Reactivation in Spite of High Levels of Induced NF-κB Activity

Kinase Control Prevents HIV-1 Reactivation in Spite of High Levels of Induced NF-κB Activity

Transient PKCα shuttling to the immunological synapse is governed by (DGK)ζ and regulates L-selectin shedding

Highly potent, synthetically accessible prostratin analogs induce latent HIV expression in vitro and ex vivo

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