The Strategies and Challenges of CCR5 Gene Editing in Hematopoietic Stem and Progenitor Cells for the Treatment of HIV

Karuppusamy, Karthik V.; Babu, Prathibha; Thangavel, Saravanabhavan

doi:10.1007/s12015-021-10145-7

Cited by 8 publications

(12 citation statements)

References 69 publications

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“…While, the approach can be used both with allogenic and autologous stem cell transplantation, the factors like graft-versus-HIV reservoir and the extensive conditioning used in allogenic stem cell transplantation may help reduce the amount of viral reservoir, independent of gene editing effect ( 58 ). However, GvHD could be a big hindrance in using allogenic graft ( 4 ). Our strategy will be limited to R5-tropic but not X4 tropic virus as we see a high expression of CXCR4 receptor in CD34 + CD90 + HSCs and this explain the reason for X4 tropic infection in the HSCs ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

“…HIV infects the immune cells through the receptors such as CD4, CCR5 and CXCR4, which are predominantly expressed on the host immune cells such as T cells, macrophages and dendritic cells ( 4 ). These receptors are the potential targets to block HIV invasion and destruction of critical immune cells ( 5 , 6 ).…”

Section: Introductionmentioning

confidence: 99%

“…To this end, gene editing tools such as Zinc Finger Nucleases (ZFN), Transcription activator like effector nucleases (TALEN) and Clustered regularly interspaced short palindromic repeats/CRISPR associated protein 9 (CRISPR/Cas9) provide alternate option for generating CCR5 edited immune cells ( 4 ). CCR5 gene editing in CD4 T cells demonstrated the protection of edited cells from HIV mediated T cell lysis in the patients ( 11 , 12 ).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, cellular senescence may deplete the frequency of modified T cells in vivo and may require repetition of the procedure ( 16 , 17 ). Though CCR5 gene editing in HSPCs can generate CCR5 null lineages, it is also associated with certain challenges ( 4 ). Unlike, gene manipulation of autologous HSPCs for genetic disorders, HSPCs obtained from infectious disease patients may also contain infectious particles.…”

Section: Introductionmentioning

confidence: 99%

“…The recent non-human primate model transplantation studies have clearly defined the immunophenotypic definition of HPCs and HSCs as CD34 + CD90 - and CD34 + CD90 + cells, respectively but how HIV infects any of these defined subpopulation remains elusive ( 20 ). There are also considerable hurdles associated with HSPC gene therapy that can negatively affect the outcome of the manipulation, such as, low frequency of HSCs in the HSPC graft, its reduction during ex vivo culture and gene editing, lack of bi-allelic gene editing in HSCs, the need to manipulate large number of HSPCs and the drop in gene editing efficiency post transplantation ( 4 ).…”

Section: Introductionmentioning

confidence: 99%

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The CCR5 Gene Edited CD34+CD90+ Hematopoietic Stem Cell Population Serves as an Optimal Graft Source for HIV Gene Therapy

et al. 2022

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Transplantation of allogenic hematopoietic stem and progenitor cells (HSPCs) with C-C chemokine receptor type 5 (CCR5) Δ32 genotype generates HIV-1 resistant immune cells. CCR5 gene edited autologous HSPCs can be a potential alternative to hematopoietic stem cell transplantation (HSCT) from HLA-matched CCR5 null donor. However, the clinical application of gene edited autologous HSPCs is critically limited by the quality of the graft, as HIV also infects the HSPCs. In this study, by using mobilized HSPCs from healthy donors, we show that the CD34+CD90+ hematopoietic stem cells (HSCs) express 7-fold lower CD4/CCR5 HIV receptors, higher levels of SAMHD1 anti-viral restriction factor, and possess lower susceptibility to HIV infection than the CD34+CD90- hematopoietic progenitor cells. Further, the treatment with small molecule cocktail of Resveratrol, UM729 and SR1(RUS) improved the in vivo engraftment potential of CD34+CD90+ HSCs. To demonstrate that CD34+CD90+ HSC population as an ideal graft for HIV gene therapy, we sort purified CD34+CD90+ HSCs, treated with RUS and then gene edited the CCR5 with single sgRNA. On transplantation, 100,000 CD34+CD90+ HSCs were sufficient for long-term repopulation of the entire bone marrow of NBSGW mice. Importantly, the gene editing efficiency of ~90% in the infused product was maintained in vivo, facilitating the generation of CCR5 null immune cells, resistant to HIV infection. Altogether, CCR5 gene editing of CD34+CD90+ HSCs provide an ideal gene manipulation strategy for autologous HSCT based gene therapy for HIV infection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

The CCR5 Gene Edited CD34+CD90+ Hematopoietic Stem Cell Population Serves as an Optimal Graft Source for HIV Gene Therapy

et al. 2022

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Gut Microbiome (Bacteria, Fungi, and Viruses) and HIV Infection: Revealing Novel Treatment Strategies

Ma,

Wen,

Dong

et al. 2023

Molecular Nutrition Food Res

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Plenty of research on microbial–viral interactions has revealed that some commensal microorganisms in the gut, including bacteria, fungi, and viruses, can resist or promote viral infection, whereas other microorganisms are involved in pathogenicity. Therefore, the balance between commensal microorganisms and human organisms is a key factor for determining infection and disease progression, and commensal microorganisms have become a hot research area in the medical field. In this review, the compositional characteristics of gut microbiota (bacteria, fungi, and viruses) during HIV infection are reviewed and changes in gut microbiota among different HIV‐infected populations are described. Furthermore, the latest progress of potential microbial therapeutic methods, including a) probiotics, prebiotics, and synbiotics, b) fecal microbiota transplantation (FMT), c) phage therapy, and d) antifungal strategy, microbial enzyme inhibition, and dietary therapeutics, is analyzed based on gut bacteria, fungi, and viruses in the field of HIV infection. This study aims to provide a useful reference for developing novel strategies for the prevention and treatment of HIV infection based on commensal microorganisms.

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A new age of precision gene therapy

Schambach,

Buchholz,

Torres-Ruiz

et al. 2024

The Lancet

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The Strategies and Challenges of CCR5 Gene Editing in Hematopoietic Stem and Progenitor Cells for the Treatment of HIV

Cited by 8 publications

References 69 publications

The CCR5 Gene Edited CD34+CD90+ Hematopoietic Stem Cell Population Serves as an Optimal Graft Source for HIV Gene Therapy

The CCR5 Gene Edited CD34+CD90+ Hematopoietic Stem Cell Population Serves as an Optimal Graft Source for HIV Gene Therapy

Gut Microbiome (Bacteria, Fungi, and Viruses) and HIV Infection: Revealing Novel Treatment Strategies

A new age of precision gene therapy

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