PR-957, a selective immunoproteasome inhibitor, reactivates latent HIV-1 through p-TEFb activation mediated by HSF-1

Lin, Jian; Zhang, Xuanxuan; Lu, Wanzhen; Xu, Xinfeng; Pan, Xiaoyan; Liang, Taizhen; Duan, Siqin; Chen, Yi; Li, Lin; Liu, Shuwen

doi:10.1016/j.bcp.2018.08.042

Cited by 14 publications

(18 citation statements)

References 39 publications

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“…Specifically, Spliceosome, Ribosome, Proteasome, and Protein export pathways from the Kyoto Encyclopedia of Genes and Genomes (KEGG), and Proteasome pathway from Biocarta database were associated with multiple dysregulated lncRNAs in both models ( Fig 4 ). Of these, proteasome function has been previously implicated in maintaining HIV in latent state, and proteasome inhibitors were proposed as LRAs [30, 31]. Among other pathways with proposed roles in HIV latent reservoir establishment or maintenance, were p53 signaling [21] and mammalian target of rapamycin (MTOR) [32].…”

Section: Resultsmentioning

confidence: 99%

Long non-coding RNAs and latent HIV – A search for novel targets for latency reversal

et al. 2019

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The latent cellular reservoir of HIV is recognized as the major barrier to cure from HIV infection. Long non-coding RNAs (lncRNAs) are more tissue and cell type-specific than protein coding genes, and may represent targets of choice for HIV latency reversal. Using two in vitro primary T-cell models, we identified lncRNAs dysregulated in latency. PVT1 and RP11-347C18.3 were up-regulated in common between the two models, and RP11-539L10.2 was down-regulated. The major component of the latent HIV reservoir, memory CD4+ T-cells, had higher expression of these lncRNAs, compared to naïve T-cells. Guilt-by-association analysis demonstrated that lncRNAs dysregulated in latency were associated with several cellular pathways implicated in HIV latency establishment and maintenance: proteasome, spliceosome, p53 signaling, and mammalian target of rapamycin (MTOR). PVT1, RP11-347C18.3, and RP11-539L10.2 were down-regulated by latency reversing agents, suberoylanilide hydroxamic acid and Romidepsin, suggesting that modulation of lncRNAs is a possible secondary mechanism of action of these compounds. These results will facilitate prioritization of lncRNAs for evaluation as targets for HIV latency reversal. Importantly, our study provides insights into regulatory function of lncRNA during latent HIV infection.

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Section: Resultsmentioning

confidence: 99%

Long non-coding RNAs and latent HIV – A search for novel targets for latency reversal

et al. 2019

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“…This finding is supported by other studies of PI in CD4+ T cells, which also showed no induction of CD69 or CD25 following PI treatment. 30,31 Thus, although bortezomib activates cells by multiple mechanisms, it does not result in global T cell activation and suggests that treatment with bortezomib will not induce systemic inflammation or cytokine storm.…”

Section: Discussionmentioning

confidence: 99%

“…The results of this study support and build upon recent work by others on the role of PIs and HIV. 25,30,31 described effects of bortezomib treatment on ELL2, a protein subunit of the super elongation complex. 30 In this report, bortezomib treatment did not affect P-TEFb levels.…”

Section: Discussionmentioning

confidence: 99%

“…11,12,21 The potential benefit of a PI, such as bortezomib, is the dual mechanisms of therapeutic HIV reactivation and inhibition of further replication of reactivated viruses. 31 To persist in cells, HIV accessory proteins target host restriction factors for proteasome mediated degradation. 32,33 In this way, use of PIs to reactivate latent HIV also prevents the ability of HIV accessory proteins to degrade host restriction factors.…”

Section: Discussionmentioning

confidence: 99%

“…30 In addition, PR-957, an inhibitor of the immunoproteasome, also reactivates latent HIV in patient cells and activates heat shock factor 1 (HSF-1) in cell lines. 31 Inhibition of the proteasome has the potential to limit further viral replication, since viral accessory proteins target host cell restriction factors, leading to their degradation by proteasomal machinery. 32,33 Taken together, proteasomal inhibition has the potential to reactivate latent HIV and limit viral replication.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Proteasomal Inhibition Potentiates Latent HIV Reactivation

Cary

Peterlin

2020

AIDS Research and Human Retroviruses

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Despite the success of antiretroviral therapy (ART), ART fails to eradicate the virus and HIV cure has remained beyond the reach of current treatments. ART targets replicating virally infected but not latently infected cells, which have limited expression of factors important for proliferation and cellular activity, including positive transcription elongation factor b (P-TEFb) and nuclear factor jB (NF-jB). Levels of the cyclin T1 (CycT1) subunit of P-TEFb are low to absent in resting T cells, and treatment with proteasome inhibitors (PIs) increases CycT1 protein levels to those of proliferating T cells. In this study, the clinically approved PI bortezomib reactivated latent HIV in latently infected primary CD4+ T cells. Bortezomib not only increased levels of CycT1 but also activated NF-jB. Strikingly, as opposed to most currently researched latency reversing agents (LRAs), bortezomib did not require a second LRA to potently reactivate latent HIV. Effects of bortezomib on resting T cells and reactivation of HIV suggest a possible direction for future attempts to diminish the viral reservoir in HIV+ individuals.

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Arsenic Trioxide Impacts Viral Latency and Delays Viral Rebound after Termination of ART in Chronically SIV‐Infected Macaques

Yang

Feng

et al. 2019

Advanced Science

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The latent viral reservoir is the source of viral rebound after interruption of antiretroviral therapy (ART) and is the major obstacle in eradicating the latent human immunodeficiency virus‐1 (HIV‐1). In this study, arsenic class of mineral, arsenic trioxide, clinically approved for treating acute promyelocytic leukemia, is demonstrated to reactivate latent provirus in CD4+ T cells from HIV‐1 patients and Simian immunodeficiency virus (SIV)‐infected macaques, without significant systemic T cell activation and inflammatory responses. In a proof‐of‐concept study using chronically SIVmac239‐infected macaques, arsenic trioxide combined with ART delays viral rebound after ART termination, reduces the integrated SIV DNA copies in CD4+ T cells, and restores CD4+ T cells counts in vivo. Most importantly, half of arsenic trioxide‐treated macaques show no detectable viral rebound in the plasma for at least 80 days after ART discontinuation. Mechanistically, the study reveals that CD4 receptors and CCR5 co‐receptors of CD4+ T cells are significantly downregulated by arsenic trioxide treatment, which reduces susceptibility to infection after provirus reactivation. Furthermore, an increase in SIV‐specific immune responses after arsenic trioxide treatment may contribute to suppression of viral rebound. This work suggests that arsenic trioxide in combination with ART is a novel regimen in down‐sizing or even eradicating latent HIV‐1 reservoir.

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PR-957, a selective immunoproteasome inhibitor, reactivates latent HIV-1 through p-TEFb activation mediated by HSF-1

Cited by 14 publications

References 39 publications

Long non-coding RNAs and latent HIV – A search for novel targets for latency reversal

Long non-coding RNAs and latent HIV – A search for novel targets for latency reversal

Proteasomal Inhibition Potentiates Latent HIV Reactivation

Arsenic Trioxide Impacts Viral Latency and Delays Viral Rebound after Termination of ART in Chronically SIV‐Infected Macaques

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