In Vivo Safety and Persistence of Endoribonuclease Gene-Transduced CD4+ T Cells in Cynomolgus Macaques for HIV-1 Gene Therapy Model

Chono, Hideto; Saito, Naoki; Tsuda, Hiroshi; Shibata, Hiroaki; Ageyama, Naohide; Terao, Keiji; Yasutomi, Yasuhiro; Mineno, Junichi; Kato, Ikunoshin

doi:10.1371/journal.pone.0023585

Cited by 20 publications

(16 citation statements)

References 38 publications

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“…Similar results were observed when the Tat-dependent MazF system were investigated on rhesus macaque primary CD4+ T cells from monkeys that were infected with the chimerical virus SHIV 89.6P (Chono et al. , 2011a , b ).…”

Section: Tas As Antiviralssupporting

confidence: 73%

“…The first report contemplates the HIV-encoded transactivator of transcription (Tat) protein, an early viral regulator, as a possible target (Chono et al. , 2011a , b ). Tat is produced early after HIV-1 infection and binds to the transactivation response (TAR) sequence, inducing the subsequent expression of other HIV-1 proteins.…”

Section: Tas As Antiviralsmentioning

confidence: 99%

“…The possible undesirable effects of MazF cleaving the eukaryotic mRNAs could be avoided by careful control of the dosage of the toxin, so that MazF was able to cleave the viral, but not damaging the cells (Chono et al. , 2011a , b ).…”

Section: Tas As Antiviralsmentioning

confidence: 99%

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One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Chan

Balsa²,

Espinosa

2015

FEMS Microbiology Reviews

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Type II (proteic) toxin–antitoxin (TA) operons are widely spread in bacteria and archaea. They are organized as operons in which, usually, the antitoxin gene precedes the cognate toxin gene. The antitoxin generally acts as a transcriptional self-repressor, whereas the toxin acts as a co-repressor, both proteins constituting a harmless complex. When bacteria encounter a stressful environment, TAs are triggered. The antitoxin protein is unstable and will be degraded by host proteases, releasing the free toxin to halt essential processes. The result is a cessation of cell growth or even death. Because of their ubiquity and the essential processes targeted, TAs have been proposed as good candidates for development of novel antimicrobials. We discuss here the possible druggability of TAs as antivirals and antibacterials, with focus on the potentials and the challenges that their use may find in the ‘real’ world. We present strategies to develop TAs as antibacterials in view of novel technologies, such as the use of very small molecules (fragments) as inhibitors of protein–protein interactions. Appropriate fragments could disrupt the T:A interfaces leading to the release of the targeted TA pair. Possible ways of delivery and formulation of Tas are also discussed.

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Section: Tas As Antiviralssupporting

confidence: 73%

Section: Tas As Antiviralsmentioning

confidence: 99%

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One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Chan

Balsa²,

Espinosa

2015

FEMS Microbiology Reviews

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“…All experiments were performed in triplicate at least three times. Values were calculated used the 2 −ΔΔCq method (25)…”

Section: Methodsmentioning

confidence: 99%

Tim-3 is upregulated in human colorectal carcinoma and associated with tumor progression

Lü

Liu

et al. 2016

Molecular Medicine Reports

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T cell immunoglobulin mucin-3 (Tim-3) has previously been implicated in the immune response and tumor biology. Colorectal carcinoma (CRC) is a malignancy, which is closely associated with inflammation. However, the role of Tim-3 in the progression of CRC remains to be fully elucidated. The present study aimed to investigate the role of Tim-3 in the progressive activities of human CRC. A total of 30 clinical CRC tissues and their adjacent tissues were collected. Slides from another 112 cases that underwent CRC surgical resection were also obtained. The protein and mRNA levels of Tim-3 in the clinical tissues and in CRC cell lines were initially examined using western blot and reverse transcription-quantitative polymerase chain reaction analyses, respectively. Immunohistochemical staining was performed to detect Tim-3 in the CRC samples. Specific small interfering (si)RNA against Tim-3 (siTim-3) was synthesized to knock down the expression of Tim-3, and the subsequent effects of Tim-3 knockdown on cell proliferation, migration and invasion were assessed. The data obtained showed that Tim-3 was expressed at high levels in the CRC tissues, compared with the non-cancerous tissues. The expression of Tim-3 in the clinical tissues was significantly associated with tumor size (P=0.007), tumor-node-metastasis staging (P<0.0001) and distant metastasis (P<0.0001). Knockdown of Tim-3 significantly reduced the cell proliferative rate of HCT116 and HT-29 cells. Wound closure activity was also inhibited by knockdown of Tim-3 in these two cell lines, and the migration and invasive abilities of these two cell lines were consistently decreased following knockdown of Tim-3. Taken together, Tim-3 was found to be a critical mediator in the progression of CRC and may serve as a potential therapeutic target for the treatment of CRC.

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“…More recently, the in vivo safety of this strategy and the persistence of the transfected CD4 ϩ cells has been tested using monkeys (5). MazF induction in mammalian cells has been shown to lead to BAK-dependent apoptotic cell death (22).…”

Section: Discussionmentioning

confidence: 99%

Intramolecular Regulation of the Sequence-Specific mRNA Interferase Activity of MazF Fused to a MazE Fragment with a Linker Cleavable by Specific Proteases

Park

Yamaguchi

Inouye

2012

Appl Environ Microbiol

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The genomes of human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) consist of single-stranded RNA encoding polyproteins, which are processed to individual functional proteins by virus-encoded specific proteases. These proteases have been used as targets for drug development. Here, instead of targeting these proteases to inhibit viral infection, we utilized the protease activity to activate a toxic protein to prevent viral infection. We engineered the MazE-MazF antitoxin-toxin system of Escherichia coli to fuse a C-terminal 41-residue fragment of antitoxin MazE to the N-terminal end of toxin MazF with a linker having a specific protease cleavage site for either HIV PR (HIV-1 protease), NS3 protease (HCV protease), or factor Xa. These fusion proteins formed a stable dimer (instead of the MazF 2 -MazE 2 -MazF 2 heterohexamer in nature) to inactivate the ACA (sequence)-specific mRNA interferase activity of MazF. When the fusion proteins were incubated with the corresponding proteases, the MazE fragment was cleaved from the fusion proteins, releasing active MazF, which then acted as an ACA-specific mRNA interferase cleaving single-stranded MS2 phage RNA. The intramolecular regulation of MazF toxicity by proteases as demonstrated may provide a novel approach for preventive and therapeutic treatments of infection by HIV-1, HCV, and other single-stranded RNA viruses.

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In Vivo Safety and Persistence of Endoribonuclease Gene-Transduced CD4+ T Cells in Cynomolgus Macaques for HIV-1 Gene Therapy Model

Cited by 20 publications

References 38 publications

One cannot rule them all: Are bacterial toxins-antitoxins druggable?

One cannot rule them all: Are bacterial toxins-antitoxins druggable?

Tim-3 is upregulated in human colorectal carcinoma and associated with tumor progression

Intramolecular Regulation of the Sequence-Specific mRNA Interferase Activity of MazF Fused to a MazE Fragment with a Linker Cleavable by Specific Proteases

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