Pre-clinical Modeling of CCR5 Knockout in Human Hematopoietic Stem Cells by Zinc Finger Nucleases Using Humanized Mice

Overview

Journal J Infect Dis

Publisher Oxford University Press

Specialty Infectious Diseases

Date 2013 Oct 24

PMID 24151324

Citations 26

Authors

Ursula Hofer

Jill E Henley

Colin M Exline

Orla Mulhern

Evan Lopez

Paula M Cannon

Affiliations

Soon will be listed here.

Abstract

Genetic strategies to block expression of CCR5, the major co-receptor of human immunodeficiency virus type 1 (HIV-1), are being developed as anti-HIV therapies. For example, human hematopoietic stem/precursor cells (HSPC) can be modified by the transient expression of CCR5-targeted zinc finger nucleases (ZFNs) to generate CCR5-negative cells, which could then give rise to HIV-resistant mature CD4(+) T cells following transplantation into patients. The safety and anti-HIV effects of such treatments can be evaluated by transplanting ZFN-treated HSPC into immunodeficient mice, where the extent of human cell engraftment, lineage differentiation and anti-HIV activity arising from the engineered HSPC can be examined. In this way, humanized mice are providing a powerful small animal model for pre-clinical studies of novel anti-HIV therapies.

Citing Articles

PlmCas12e (CasX2) cleavage of CCR5: impact of guide RNA spacer length and PAM sequence on cleavage activity.

Armstrong D, Hudson T, Hodge C, Hampton T, Howell A, Hayden M RNA Biol. 2023; 20(1):296-305.

PMID: 37287312 PMC: 10251783. DOI: 10.1080/15476286.2023.2221510.

Progress in and Prospects of Genome Editing Tools for Human Disease Model Development and Therapeutic Applications.

Phan H, Kim K, Lee H, Seong J Genes (Basel). 2023; 14(2).

PMID: 36833410 PMC: 9957140. DOI: 10.3390/genes14020483.

CAS12e (CASX2) CLEAVAGE OF CCR5: IMPACT OF GUIDE RNA LENGTH AND PAM SEQUENCE ON CLEAVAGE ACTIVITY.

Armstrong D, Hudson T, Hodge C, Hampton T, Howell A, Hayden M bioRxiv. 2023; .

PMID: 36711562 PMC: 9881857. DOI: 10.1101/2023.01.02.522476.

Advancing our understanding of HIV co-infections and neurological disease using the humanized mouse.

Endsley J, Huante M, Naqvi K, Gelman B, Endsley M Retrovirology. 2021; 18(1):14.

PMID: 34134725 PMC: 8206883. DOI: 10.1186/s12977-021-00559-z.

Increased Efficiency for Biallelic Mutations of the Gene by CRISPR-Cas9 Using Multiple Guide RNAs As a Novel Therapeutic Option for Human Immunodeficiency Virus.

Lin D, Scheller S, Robinson M, Izadpanah R, Alt E, Braun S CRISPR J. 2021; 4(1):92-103.

PMID: 33616448 PMC: 8713505. DOI: 10.1089/crispr.2020.0019.

References

Urnov F, Miller J, Lee Y, Beausejour C, Rock J, Augustus S . Highly efficient endogenous human gene correction using designed zinc-finger nucleases. Nature. 2005; 435(7042):646-51. DOI: 10.1038/nature03556. View

Ringpis G, Shimizu S, Arokium H, Camba-Colon J, Carroll M, Cortado R . Engineering HIV-1-resistant T-cells from short-hairpin RNA-expressing hematopoietic stem/progenitor cells in humanized BLT mice. PLoS One. 2013; 7(12):e53492. PMC: 3534037. DOI: 10.1371/journal.pone.0053492. View

Neff C, Zhou J, Remling L, Kuruvilla J, Zhang J, Li H . An aptamer-siRNA chimera suppresses HIV-1 viral loads and protects from helper CD4(+) T cell decline in humanized mice. Sci Transl Med. 2011; 3(66):66ra6. PMC: 3138523. DOI: 10.1126/scitranslmed.3001581. View

Leung W, Ramirez M, Novelli E, Civin C . In vivo engraftment potential of clinical hematopoietic grafts. J Investig Med. 1998; 46(6):303-11. View

Yukl S, Boritz E, Busch M, Bentsen C, Chun T, Douek D . Challenges in detecting HIV persistence during potentially curative interventions: a study of the Berlin patient. PLoS Pathog. 2013; 9(5):e1003347. PMC: 3649997. DOI: 10.1371/journal.ppat.1003347. View

Perez E, Wang J, Miller J, Jouvenot Y, Kim K, Liu O . Establishment of HIV-1 resistance in CD4+ T cells by genome editing using zinc-finger nucleases. Nat Biotechnol. 2008; 26(7):808-16. PMC: 3422503. DOI: 10.1038/nbt1410. View

Horn P, Thomasson B, Wood B, Andrews R, Morris J, Kiem H . Distinct hematopoietic stem/progenitor cell populations are responsible for repopulating NOD/SCID mice compared with nonhuman primates. Blood. 2003; 102(13):4329-35. DOI: 10.1182/blood-2003-01-0082. View

Cannon P, June C . Chemokine receptor 5 knockout strategies. Curr Opin HIV AIDS. 2011; 6(1):74-9. PMC: 3066441. DOI: 10.1097/COH.0b013e32834122d7. View

Wu L, Gerard N, Wyatt R, Choe H, Parolin C, Ruffing N . CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature. 1996; 384(6605):179-83. DOI: 10.1038/384179a0. View

10.

Glass W, McDermott D, Lim J, Lekhong S, Yu S, Frank W . CCR5 deficiency increases risk of symptomatic West Nile virus infection. J Exp Med. 2006; 203(1):35-40. PMC: 2118086. DOI: 10.1084/jem.20051970. View

11.

Mezquita P, Beard B, Kiem H . NOD/SCID repopulating cells contribute only to short-term repopulation in the baboon. Gene Ther. 2008; 15(21):1460-2. DOI: 10.1038/gt.2008.108. View

12.

Shimizu S, Hong P, Arumugam B, Pokomo L, Boyer J, Koizumi N . A highly efficient short hairpin RNA potently down-regulates CCR5 expression in systemic lymphoid organs in the hu-BLT mouse model. Blood. 2009; 115(8):1534-44. PMC: 2830759. DOI: 10.1182/blood-2009-04-215855. View

13.

Akkina R . New generation humanized mice for virus research: comparative aspects and future prospects. Virology. 2012; 435(1):14-28. PMC: 3932328. DOI: 10.1016/j.virol.2012.10.007. View

14.

Hutter G, Nowak D, Mossner M, Ganepola S, Mussig A, Allers K . Long-term control of HIV by CCR5 Delta32/Delta32 stem-cell transplantation. N Engl J Med. 2009; 360(7):692-8. DOI: 10.1056/NEJMoa0802905. View

15.

Angelopoulou M, Rinder H, Wang C, Burtness B, Cooper D, Krause D . A preclinical xenotransplantation animal model to assess human hematopoietic stem cell engraftment. Transfusion. 2004; 44(4):555-66. DOI: 10.1111/j.1537-2995.2004.03285.x. View

16.

Allers K, Hutter G, Hofmann J, Loddenkemper C, Rieger K, Thiel E . Evidence for the cure of HIV infection by CCR5Δ32/Δ32 stem cell transplantation. Blood. 2010; 117(10):2791-9. DOI: 10.1182/blood-2010-09-309591. View

17.

Lepus C, Gibson T, Gerber S, Kawikova I, Szczepanik M, Hossain J . Comparison of human fetal liver, umbilical cord blood, and adult blood hematopoietic stem cell engraftment in NOD-scid/gammac-/-, Balb/c-Rag1-/-gammac-/-, and C.B-17-scid/bg immunodeficient mice. Hum Immunol. 2009; 70(10):790-802. PMC: 2949440. DOI: 10.1016/j.humimm.2009.06.005. View

18.

Joseph A, Zheng J, Chen K, Dutta M, Chen C, Stiegler G . Inhibition of in vivo HIV infection in humanized mice by gene therapy of human hematopoietic stem cells with a lentiviral vector encoding a broadly neutralizing anti-HIV antibody. J Virol. 2010; 84(13):6645-53. PMC: 2903239. DOI: 10.1128/JVI.02339-09. View

19.

Boyman O, Purton J, Surh C, Sprent J . Cytokines and T-cell homeostasis. Curr Opin Immunol. 2007; 19(3):320-6. DOI: 10.1016/j.coi.2007.04.015. View

20.

Shultz L, Lyons B, Burzenski L, Gott B, Chen X, Chaleff S . Human lymphoid and myeloid cell development in NOD/LtSz-scid IL2R gamma null mice engrafted with mobilized human hemopoietic stem cells. J Immunol. 2005; 174(10):6477-89. DOI: 10.4049/jimmunol.174.10.6477. View