CRISPR/Cas9-Mediated CCR5 Ablation in Human Hematopoietic Stem/Progenitor Cells Confers HIV-1 Resistance In Vivo

Xu, Lei; Yang, Huan; Gao, Yang; Chen, Zeyu; Xie, Liangfu; Liu, Yulin; Liu, Ying; Wang, Xiaobao; Li, Hanwei; Lai, Weifeng; He, Yuan; Yao, Anzhi; Ma, Liying; Shao, Yiming; Zhang, Bin; Wang, Chengyan; Hu, Chen; Deng, Hongkui

doi:10.1016/j.ymthe.2017.04.027

Cited by 201 publications

(188 citation statements)

References 23 publications

(37 reference statements)

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“…Several prior studies have also focused on knocking out the HIV co-receptors, CCR5 and CXCR4, as a means to block viral spread. As expected, CRISPR-Cas9-mediated knockout of the CCR5 gene inhibited HIV-1 infection in induced pluripotent stem cell-derived monocyte/macrophages [237], primary CD4+ T cells [238], and in vivo [239,240]. Similarly, CXCR4 knockout was shown to confer resistance to X4-tropic virus infection [241][242][243].…”

Section: Crisprsupporting

confidence: 66%

Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy

Schwarzer

Gramatica

Greene

2020

Viruses

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Human immunodeficiency virus (HIV-1) indefinitely persists, despite effective antiretroviral therapy (ART), within a small pool of latently infected cells. These cells often display markers of immunologic memory and harbor both replication-competent and -incompetent proviruses at approximately a 1:100 ratio. Although complete HIV eradication is a highly desirable goal, this likely represents a bridge too far for our current and foreseeable technologies. A more tractable goal involves engineering a sustained viral remission in the absence of ART--a "functional cure." In this setting, HIV remains detectable during remission, but the size of the reservoir is small and the residual virus is effectively controlled by an engineered immune response or other intervention. Biological precedence for such an approach is found in the post-treatment controllers (PTCs), a rare group of HIV-infected individuals who, following ART withdrawal, do not experience viral rebound. PTCs are characterized by a small reservoir, greatly reduced inflammation, and the presence of a poorly understood immune response that limits viral rebound. Our goal is to devise a safe and effective means for replicating durable post-treatment control on a global scale. This requires devising methods to reduce the size of the reservoir and to control replication of this residual virus. In the following sections, we will review many of the approaches and tools that likely will be important for implementing such a "reduce and control" strategy and for achieving a PTC-like sustained HIV remission in the absence of ART.

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Section: Crisprsupporting

confidence: 66%

Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy

Schwarzer

Gramatica

Greene

2020

Viruses

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“…For example, a naturally occurring deletion in the CCR5 gene encoding an essential coreceptor of HIV confers resistance to HIV infection, providing the basis of cell therapy against HIV infection (Hendel et al 2015;Hultquist et al 2016;Xu et al 2017). …”

Section: Discussionmentioning

confidence: 99%

CRISPR RNAs trigger innate immune responses in human cells

et al. 2018

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Here, we report that CRISPR guide RNAs (gRNAs) with a 5 ′ -triphosphate group (5 ′ -ppp gRNAs) produced via in vitro transcription trigger RNA-sensing innate immune responses in human and murine cells, leading to cytotoxicity. 5 ′ -ppp gRNAs in the cytosol are recognized by DDX58, which in turn activates type I interferon responses, causing up to ∼80% cell death. We show that the triphosphate group can be removed by a phosphatase in vitro and that the resulting 5 ′ -hydroxyl gRNAs in complex with Cas9 or Cpf1 avoid innate immune responses and can achieve targeted mutagenesis at a frequency of 95% in primary human CD4 + T cells. These results are in line with previous findings that chemically synthesized sgRNAs with a 5 ′ -hydroxyl group are much more efficient than in vitro-transcribed (IVT) sgRNAs in human and other mammalian cells. The phosphatase treatment of IVT sgRNAs is a cost-effective method for making highly active sgRNAs, avoiding innate immune responses in human cells.

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“…Such studies address the CCR5 molecule per se (Castanheira et al, 2019; Jiao et al, 2018; Liu et al, 2018; Umansky, Blattner, Gebhardt, & Utikal, 2017), CCR5 pharmacological blockade (Moy et al, 2017; Pervaiz et al, 2019), CCR5 gene editing (Xie, Zhan, Ge, & Tang, 2019) and the genetic variant CCR5Δ32 (Fatima et al, 2019; Kaminski, Ellwanger, Sandrim, Pontillo, & Chies, 2019; Kletenkov et al, 2019; Słomiński et al, 2017; Toson et al, 2017; Troncoso et al, 2018). The resurgence of research involving these different aspects of CCR5 is due to two main factors: the advancement of gene‐editing technologies, which allow the exploration of the metabolic and pathophysiological effects of CCR5 editing (Allen et al, 2018; Qi et al, 2018; Vangelista & Vento, 2018; Xu et al, 2017), and the development of CCR5 blockers for clinical use (Vangelista & Vento, 2018). Recently, the different effects of CCR5 editing were much debated (Ellwanger, Kaminski, & Chies, 2019; Wang & Yang, 2019; Xie et al, 2019) after a Chinese scientist alleged to had performed this procedure on human embryos (Cyranoski & Ledford, 2018).…”

Section: Introductionmentioning

confidence: 99%

CCR5 and CCR5Δ32 in bacterial and parasitic infections: Thinking chemokine receptors outside the HIV box

Ellwanger

Kaminski

Rodrigues

et al. 2020

Int J Immunogenetics

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The CCR5 molecule was reported in 1996 as the main HIV‐1 co‐receptor. In that same year, the CCR5Δ32 genetic variant was described as a strong protective factor against HIV‐1 infection. These findings led to extensive research regarding the CCR5, culminating in critical scientific advances, such as the development of CCR5 inhibitors for the treatment of HIV infection. Recently, the research landscape surrounding CCR5 has begun to change. Different research groups have realized that, since CCR5 has such important effects in the chemokine system, it could also affect other different physiological systems. Therefore, the effect of reduced CCR5 expression due to the presence of the CCR5Δ32 variant began to be further studied. Several studies have investigated the role of CCR5 and the impacts of CCR5Δ32 on autoimmune and inflammatory diseases, various types of cancer, and viral diseases. However, the role of CCR5 in diseases caused by bacteria and parasites is still poorly understood. Therefore, the aim of this article is to review the role of CCR5 and the effects of CCR5Δ32 on bacterial (brucellosis, osteomyelitis, pneumonia, tuberculosis and infection by Chlamydia trachomatis) and parasitic infections (toxoplasmosis, leishmaniasis, Chagas disease and schistosomiasis). Basic information about each of these infections was also addressed. The neglected role of CCR5 in fungal disease and emerging studies regarding the action of CCR5 on regulatory T cells are briefly covered in this review. Considering the “renaissance of CCR5 research,” this article is useful for updating researchers who develop studies involving CCR5 and CCR5Δ32 in different infectious diseases.

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CRISPR/Cas9-Mediated CCR5 Ablation in Human Hematopoietic Stem/Progenitor Cells Confers HIV-1 Resistance In Vivo

Cited by 201 publications

References 23 publications

Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy

Reduce and Control: A Combinatorial Strategy for Achieving Sustained HIV Remissions in the Absence of Antiretroviral Therapy

CRISPR RNAs trigger innate immune responses in human cells

CCR5 and CCR5Δ32 in bacterial and parasitic infections: Thinking chemokine receptors outside the HIV box

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