BIRC2/cIAP1 Is a Negative Regulator of HIV-1 Transcription and Can Be Targeted by Smac Mimetics to Promote Reversal of Viral Latency

Pache, Lars; Dutra, Míriam Santos; Spivak, Adam M.; Marlett, John; Murry, Jeffrey P.; Hwang, Young Sun; Maestre, Ana; Manganaro, Lara; Vamos, Mitchell; Teriete, Peter; Martins, Laura J.; König, Renate; Simon, Viviana; Bosque, Alberto; Fernández-Sesma, Ana; Cosford, Nicholas D. P.; Bushman, Frederic D.; Young, John A. T.; Planelles, Vicente; Chanda, Sumit K.

doi:10.1016/j.chom.2015.08.009

Cited by 121 publications

(167 citation statements)

References 35 publications

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“…Most Smac proteins directly compete with caspases for XIAP binding, liberating caspases for apoptosis. Smac proteins can also activate the ubiquitin activity of cIAP1/2 leading to the degradation of these IAPs (Pache et al, 2015). Through their ability to bind and inhibit IAP activity, Smac mimetics can induce pro-apoptotic mechanisms and therefore are attractive compounds to induce the apoptosis of reactivated, latently infected cells.…”

Section: Pro-apoptotic Compounds To Clear Hiv Latently Infected T-cellsmentioning

confidence: 99%

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

Kim

Anderson

Lewin

2018

Cell Host & Microbe

312

351

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Despite the success of antiretroviral therapy (ART), there is currently no HIV cure and treatment is lifelong. HIV persists during ART due to long lived and proliferating latently infected CD4+ T-cells. One strategy to eliminate latency is to activate virus production using latency reversing agents (LRAs) with the goal of triggering cell death through virus-induced cytolysis or immune-mediated clearance. However, multiple studies have demonstrated that activation of viral transcription alone is insufficient to induce cell death and some LRAs may counteract cell death by promoting cell survival. Here, we review new approaches to induce death of latently infected cells through apoptosis and inhibition of pathways critical for cell survival, which are often hijacked by HIV proteins. Given advances in the commercial development of compounds that induce apoptosis in cancer chemotherapy, these agents could move rapidly into clinical trials, either alone or in combination with LRAs, to eliminate latent HIV infection.

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Section: Pro-apoptotic Compounds To Clear Hiv Latently Infected T-cellsmentioning

confidence: 99%

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

Kim

Anderson

Lewin

2018

Cell Host & Microbe

312

351

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“…Inhibition of cIAP1 by SMAC mimetics leads to the accumulation of NIK, phosphorylation of IKKα, and the subsequent processing of p100 to p52. RelB/p52 heterodimers then translocate to the nucleus where they induce NF-κB-dependent transcription, including triggering transcription of latent proviruses (81). In vitro studies of HDAC inhibitor/SMAC/XIAP mimetic combinations demonstrated potent synergistic activities between these two classes of compounds(81).…”

Section: Smac Mimetics and The Non-canonical Nf-κb Activation Pathwaymentioning

confidence: 99%

Novel Latency Reversal Agents for HIV-1 Cure

2018

Self Cite

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Antiretroviral therapy (ART) has rendered HIV-1 infection a treatable illness, however ART is not curative due to the persistence of replication-competent, latent proviruses in long-lived resting T cells. Strategies that target these latently infected cells and allow for immune recognition and clearance of this reservoir will be necessary to eradicate HIV-1 in infected individuals. This review describes current pharmacologic approaches to reactivate the latent reservoir in a manner that infected cells can be recognized and targeted, with the ultimate goal of achieving an HIV-1 cure.

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“…Recently, IAP1/2 and survivin, another member of the IAP family were suggested to be involved in survival of HIV-infected CD4+ T cells [46,47]. In addition, IAPs have been implicated in protection against hepatitis B infection and in the reversal of HIV latency in CD4+ T cells [48,49]. Using HIV-Vpr as an apoptosis-inducing agent, we have shown a protective role for IAP genes in resistance to cell death in Mφ [50][51][52].…”

Section: Introductionmentioning

confidence: 86%

“…Apoptosis has been shown to induce viral activation and replication in latently infected U1 and ACH2 cell lines [56]. In addition, Pache et al have shown that SMs can affect viral transcription in infected CD4 + T cells via NF-κB dependent signalling [49]. To determine if SMs affect HIV replication in Mϕ, in vitro HIV-infected MDM were treated with SM -LCL161 for 48 hr followed by analysis of p24 secretion.…”

Section: Sms Induce Cell Death In In Vitro Hiv-infected Mdms and Mdmsmentioning

confidence: 99%

Inhibitor of apoptosis, IAP, genes play a critical role in the survival of HIV-infected macrophages

Kumar

Reh

Sxm

et al. 2019

Preprint

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Latent viral reservoirs of HIV-1 that persist despite antiretroviral therapy (ART) are major barriers for a successful cure. Macrophages serve as viral reservoirs due to their resistance to apoptosis and HIV-cytopathic effects. We have previously shown that inhibitor of apoptosis proteins (IAPs) confer resistance to HIV-Vpr-induced apoptosis in normal macrophages. Herein, we show that second mitochondrial activator of caspases (SMAC)-mimetics (SM) specifically induce apoptosis of monocyte-derived macrophages (MDMs) infected in vitro with a R5-tropic laboratory strain expressing heat stable antigen, and GFP-expressing HIV, chronically infected U1 cells, and ex-vivo derived MDMs from naïve and ART-treated HIV patients. SM-induced cell death was found to be mediated by IAPs using IAP siRNAs, was independent of endogenously produced TNFα and was attributed to the concomitant downregulation of IAP-1/2 and the receptor interacting protein kinase-1 degradation following HIV infection. Altogether, modulation of the IAP pathways may be a potential strategy for selective killing of HIV-infected macrophages in vivo.

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BIRC2/cIAP1 Is a Negative Regulator of HIV-1 Transcription and Can Be Targeted by Smac Mimetics to Promote Reversal of Viral Latency

Cited by 121 publications

References 35 publications

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

Getting the “Kill” into “Shock and Kill”: Strategies to Eliminate Latent HIV

Novel Latency Reversal Agents for HIV-1 Cure

Inhibitor of apoptosis, IAP, genes play a critical role in the survival of HIV-infected macrophages

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