Long-term Vector Integration Site Analysis Following Retroviral Mediated Gene Transfer to Hematopoietic Stem Cells for the Treatment of HIV Infection

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2009 Jan 17

PMID 19148292

Citations 12

Authors

Jun Hayakawa

Kareem Washington

Naoya Uchida

Oswald Phang

Elizabeth M Kang

Matthew M Hsieh

John F Tisdale

Affiliations

Soon will be listed here.

Abstract

We previously reported the efficacy of nonmyeloablative allogeneic transplantation in 2 HIV positive recipients, one of whom received retrovirus transduced hematopoietic stem cells to confer resistance to HIV. Here we report an assessment of retroviral integration sites (RISs) recovered out to 3 years post-transplantation. We identified 213 unique RISs from the patient's peripheral blood samples by linear amplification-mediated PCR (LAM-PCR). While vector integration patterns were similar to that previously reported, only 3.76% of RISs were common among early (up to 3 months) and late samples (beyond 1 year). Additionally, common integration sites were enriched among late samples (14.9% vs. 36.8%, respectively). Three RISs were found near or within known oncogenes, but 2 were limited to early timepoints. Interestingly, an integration site near the MDS1 gene was detected in long-term follow-up samples; however, the overall contribution of MDS1 integrated clone remained stably low during follow-up.

Citing Articles

Mechanisms and Cardiorenal Complications of Chronic Anemia in People with HIV.

Kamvuma K, Hamooya B, Munsaka S, Masenga S, Kirabo A Viruses. 2024; 16(4).

PMID: 38675885 PMC: 11053456. DOI: 10.3390/v16040542.

MECOM Deficiency: from Bone Marrow Failure to Impaired B-Cell Development.

Voit R, Sankaran V J Clin Immunol. 2023; 43(6):1052-1066.

PMID: 37407873 DOI: 10.1007/s10875-023-01545-0.

Development and clinical translation of gene therapy.

Wu X, He X, Liu F, Jiang X, Wang P, Zhang J Comput Struct Biotechnol J. 2022; 20:2986-3003.

PMID: 35782737 PMC: 9218169. DOI: 10.1016/j.csbj.2022.06.015.

RNA Interference Therapies for an HIV-1 Functional Cure.

Scarborough R, Gatignol A Viruses. 2017; 10(1).

PMID: 29280961 PMC: 5795421. DOI: 10.3390/v10010008.

Ub-ISAP: a streamlined UNIX pipeline for mining unique viral vector integration sites from next generation sequencing data.

Kamboj A, Hallwirth C, Alexander I, McCowage G, Kramer B BMC Bioinformatics. 2017; 18(1):305.

PMID: 28623888 PMC: 5474025. DOI: 10.1186/s12859-017-1719-4.

References

Schwarzwaelder K, Howe S, Schmidt M, Brugman M, Deichmann A, Glimm H . Gammaretrovirus-mediated correction of SCID-X1 is associated with skewed vector integration site distribution in vivo. J Clin Invest. 2007; 117(8):2241-9. PMC: 1934556. DOI: 10.1172/JCI31661. View

Kustikova O, Geiger H, Li Z, Brugman M, Chambers S, Shaw C . Retroviral vector insertion sites associated with dominant hematopoietic clones mark "stemness" pathways. Blood. 2006; 109(5):1897-907. PMC: 1801061. DOI: 10.1182/blood-2006-08-044156. View

Metais J, Dunbar C . The MDS1-EVI1 gene complex as a retrovirus integration site: impact on behavior of hematopoietic cells and implications for gene therapy. Mol Ther. 2008; 16(3):439-49. DOI: 10.1038/sj.mt.6300372. View

Schmidt M, Schwarzwaelder K, Bartholomae C, Zaoui K, Ball C, Pilz I . High-resolution insertion-site analysis by linear amplification-mediated PCR (LAM-PCR). Nat Methods. 2007; 4(12):1051-7. DOI: 10.1038/nmeth1103. 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

Senchenko V, Liu J, Loginov W, Bazov I, Angeloni D, Seryogin Y . Discovery of frequent homozygous deletions in chromosome 3p21.3 LUCA and AP20 regions in renal, lung and breast carcinomas. Oncogene. 2004; 23(34):5719-28. DOI: 10.1038/sj.onc.1207760. View

Tisdale J, Hanazono Y, Sellers S, Agricola B, Metzger M, Donahue R . Ex vivo expansion of genetically marked rhesus peripheral blood progenitor cells results in diminished long-term repopulating ability. Blood. 1998; 92(4):1131-41. View

Cavazzana-Calvo M, de Saint Basile G, Gross F, Yvon E, Nusbaum P, Selz F . Gene therapy of human severe combined immunodeficiency (SCID)-X1 disease. Science. 2000; 288(5466):669-72. DOI: 10.1126/science.288.5466.669. View

Deichmann A, Hacein-Bey-Abina S, Schmidt M, Garrigue A, Brugman M, Hu J . Vector integration is nonrandom and clustered and influences the fate of lymphopoiesis in SCID-X1 gene therapy. J Clin Invest. 2007; 117(8):2225-32. PMC: 1934585. DOI: 10.1172/JCI31659. View

10.

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

11.

Wu X, Li Y, Crise B, Burgess S . Transcription start regions in the human genome are favored targets for MLV integration. Science. 2003; 300(5626):1749-51. DOI: 10.1126/science.1083413. View

12.

Hacein-Bey-Abina S, von Kalle C, Schmidt M, McCormack M, Wulffraat N, Leboulch P . LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003; 302(5644):415-9. DOI: 10.1126/science.1088547. View

13.

Suzuki T, Shen H, Akagi K, Morse H, Malley J, Naiman D . New genes involved in cancer identified by retroviral tagging. Nat Genet. 2002; 32(1):166-74. DOI: 10.1038/ng949. View

14.

Mitchell R, Beitzel B, Schroder A, Shinn P, Chen H, Berry C . Retroviral DNA integration: ASLV, HIV, and MLV show distinct target site preferences. PLoS Biol. 2004; 2(8):E234. PMC: 509299. DOI: 10.1371/journal.pbio.0020234. View

15.

Aiuti A, Cassani B, Andolfi G, Mirolo M, Biasco L, Recchia A . Multilineage hematopoietic reconstitution without clonal selection in ADA-SCID patients treated with stem cell gene therapy. J Clin Invest. 2007; 117(8):2233-40. PMC: 1934603. DOI: 10.1172/JCI31666. View

16.

Christensen C, Ambartsumian N, Gilestro G, Thomsen B, Comoglio P, Tamagnone L . Proteolytic processing converts the repelling signal Sema3E into an inducer of invasive growth and lung metastasis. Cancer Res. 2005; 65(14):6167-77. DOI: 10.1158/0008-5472.CAN-04-4309. View

17.

Hacein-Bey-Abina S, Garrigue A, Wang G, Soulier J, Lim A, Morillon E . Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest. 2008; 118(9):3132-42. PMC: 2496963. DOI: 10.1172/JCI35700. View

18.

Kang E, de Witte M, Malech H, Morgan R, Carter C, Leitman S . Gene therapy-based treatment for HIV-positive patients with malignancies. J Hematother Stem Cell Res. 2002; 11(5):809-16. DOI: 10.1089/152581602760404612. View

19.

Baum C, Dullmann J, Li Z, Fehse B, Meyer J, Williams D . Side effects of retroviral gene transfer into hematopoietic stem cells. Blood. 2003; 101(6):2099-114. DOI: 10.1182/blood-2002-07-2314. View

20.

Calin G, Trapasso F, Shimizu M, Dumitru C, Yendamuri S, Godwin A . Familial cancer associated with a polymorphism in ARLTS1. N Engl J Med. 2005; 352(16):1667-76. DOI: 10.1056/NEJMoa042280. View