Inhibition of HIV-1 infection of primary CD4+ T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9

Li, Chang; Guan, Xiangguo; Du, Tao; Jin, Wei; Wu, Bingcheng; Liu, Yalan; Wang, Ping; Hu, Bodan; Griffin, George E.; Shattock, Robin J.; Hu, Qinxue

doi:10.1099/vir.0.000139

Cited by 184 publications

(150 citation statements)

References 71 publications

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“…26 Chang Li also used this method with CD4 C T cells on CCR5 gene knockout to inhibit HIV replication. 27 However, gene editing of immune checkpoints is rarely documented in relevant literature. In our previous studies, we described, for the first time, a new approach of inhibiting PD-1/PD-L1 co-stimulation by directly disrupting genome PD-1 expression on primary T cells from cancer patients through the CRISPR-Cas9 system.…”

Section: Discussionmentioning

confidence: 99%

CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer

Zou

Chen

et al. 2016

OncoImmunology

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The successful use of immune cell checkpoint inhibitors PD-1 and PD-L1, over the past 5 y has raised the concern of using immunotherapy to treat various cancers. Epstein-Barr virus-associated gastric cancer (EBVaGC) exhibits high infiltration of lymphocytes and high amplification of immune-related genes including PD-L1 as distinguished from Epstein-Barr virus-non-associated gastric cancer (EBVnGC). Here, we presume that this PD-1/PD-L1 pathway may hinder the efficacy of adoptive T cell therapy toward EBVaGC. These studies reveal possibility of generating PD-1-disrupted CTL by CRISPR-Cas9 system and demonstrate enhanced immune response of these PD-1-disrupted CTLs to the EBV-LMP2A antigen and superior cytotoxicity to the EBV-positive gastric cancer cell. In addition, when combined with low-dose radiotherapy, these PD-1-disrupted CTLs mediated an impressive antitumor effect in a xenograft mouse model of EBVaGC. Taken together, these studies illustrate PD-1/PD-L1-mediated immune tolerance of EBVaGC and provide a new strategy for targeting immune checkpoints to break the tolerance for the T cell-based adoptive therapy.

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Section: Discussionmentioning

confidence: 99%

CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer

Zou

Chen

et al. 2016

OncoImmunology

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“…59,60 One potential advantage of CRISPR/Cas9 is that multiple guide RNAs can be used simultaneously to potentiate the magnitude of gene disruption or to induce specific deletions that are larger than the typical indels generated by NHEJ. 59 However such multicomponent systems (requiring nuclease and guide RNAs) may introduce complexity into the clinical development process, and clinically suitable methods to deliver CRISPR/Cas9 to HSPCs in particular are still under development.…”

Section: Future Approaches To Gene Disruptionmentioning

confidence: 99%

The clinical applications of genome editing in HIV

Wang

Cannon

2016

Blood

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HIV/AIDS has long been at the forefront of the development of gene- and cell-based therapies. Although conventional gene therapy approaches typically involve the addition of anti-HIV genes to cells using semirandomly integrating viral vectors, newer genome editing technologies based on engineered nucleases are now allowing more precise genetic manipulations. The possible outcomes of genome editing include gene disruption, which has been most notably applied to the CCR5 coreceptor gene, or the introduction of small mutations or larger whole gene cassette insertions at a targeted locus. Disruption of CCR5 using zinc finger nucleases was the first-in-human application of genome editing and remains the most clinically advanced platform, with 7 completed or ongoing clinical trials in T cells and hematopoietic stem/progenitor cells (HSPCs). Here we review the laboratory and clinical findings of CCR5 editing in T cells and HSPCs for HIV therapy and summarize other promising genome editing approaches for future clinical development. In particular, recent advances in the delivery of genome editing reagents and the demonstration of highly efficient homology-directed editing in both T cells and HSPCs are expected to spur the development of even more sophisticated applications of this technology for HIV therapy.

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“…Dual gRNAs resulted in doubled efficiency from 12.5% to 27% of cell colonies and 22.2% to 41% biallelic editing [22]. Delivery systems were recently discussed about in a comprehensive study on primary CD4+ T cell manipulation [23].…”

Section: Methods For Blocking the Entry Of Hiv-1 Into Cells Editing Cmentioning

confidence: 99%

CRISPRs encounter Cocktail: a dawn for curing HIV/AIDS

Li¹,

Zhang²,

Feng³

et al. 2017

Virol Res Rev

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a These authors contributed equally to this work. AbstractThe acquired immunodeficiency syndrome (AIDS) patients can scarcely be cured completely because of the Human Immunodeficiency Virus (HIV) provirus existence post-infection in body, though cocktail of the highly active antiretroviral therapy (HAART) has achieved great effects on controlling and decreasing HIV clinically. Recently, the genome editing strategies are developing by leaps and bounds. Among three generation of technologies, the clustered regularly interspaced short palindromic repeat (CRISPR)-CRISPR-associated protein 9 (Cas9) is a newborn to former zinc finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) but grows fast into the most popular at present, because of its advantages in less time-and cost-consuming. Eradicating HIV by disrupting the viral co-receptor C-C chemokine receptor type five (CCR5) or C-X-C chemokine receptor type four (CXCR4) gene, excising the provirus segments integrated into human genome, or activating/inactivating the replication of the virus genome by using these technologies are several current strategies to reach the goal of AIDS prevention and treatment. It seems hard, however, to arrive the keen anticipation exactly by using them respectively. After a comprehensive literature review, it concluded that the combination of those interventions, as together co-receptor with provirus genome interference as a cocktail edition, may lead us to an eventual cure for the horrible disease.

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Inhibition of HIV-1 infection of primary CD4+ T-cells by gene editing of CCR5 using adenovirus-delivered CRISPR/Cas9

Cited by 184 publications

References 71 publications

CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer

CRISPR-Cas9-mediated disruption of PD-1 on human T cells for adoptive cellular therapies of EBV positive gastric cancer

The clinical applications of genome editing in HIV

CRISPRs encounter Cocktail: a dawn for curing HIV/AIDS

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