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J Exp Med. 1992 October 1; 176(4): 1125–1135.
PMCID: PMC2119385

Helper virus induced T cell lymphoma in nonhuman primates after retroviral mediated gene transfer

Abstract

Moloney Murine Leukemia Virus (MoMuLV) causes T cell neoplasms in rodents but is not known to be a pathogen in primates. The core protein and enzyme genes of the MoMuLV genome together with an amphotropic envelope gene are utilized to engineer the cell lines that generate retroviral vectors for use in current human gene therapy applications. We developed a producer clone that generates a very high concentration of retroviral vector particles to optimize conditions for gene insertion into pluripotent hematopoietic stem cells. This producer cell line also generates a much lower concentration of replication-competent virus that arose through recombination. Stem cells from rhesus monkeys were purified by immunoselection with an anti-CD34 antibody, incubated in vitro for 80-86 h in the presence of retroviral vector particles with accompanying replication-competent virus and used to reconstitute recipients whose bone marrow had been ablated by total body irradiation. The retroviral vector genome was detected in circulating cells of five of eight transplant recipients of CD34+ cells and in the circulating cells of two recipients of infected, unfractionated bone marrow mononuclear cells. Three recipients of CD34+ cells had a productive infection with replication-competent virus. Six or seven mo after transplantation, each of these animals developed a rapidly progressive T cell neoplasm involving the thymus, lymph nodes, liver, spleen, and bone marrow. Lymphoma cells contained 10-50 copies of the replication-competent virus, but lacked the retroviral vector genome. We conclude that replication-competent viruses arising from producer cells making retroviral vectors can be pathogenic in primates, which underscores the importance of carefully screening retroviral producer clones used in human trials to exclude contamination with replication- competent virus.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Miller AD, Rosman GJ. Improved retroviral vectors for gene transfer and expression. Biotechniques. 1989 Oct;7(9):980–990. [PMC free article] [PubMed]
  • Linial ML, Miller AD. Retroviral RNA packaging: sequence requirements and implications. Curr Top Microbiol Immunol. 1990;157:125–152. [PubMed]
  • Culver KW, Anderson WF, Blaese RM. Lymphocyte gene therapy. Hum Gene Ther. 1991 Summer;2(2):107–109. [PubMed]
  • Tsichlis PN, Lazo PA. Virus-host interactions and the pathogenesis of murine and human oncogenic retroviruses. Curr Top Microbiol Immunol. 1991;171:95–171. [PubMed]
  • Tsichlis PN. Oncogenesis by Moloney murine leukemia virus. Anticancer Res. 1987 Mar-Apr;7(2):171–180. [PubMed]
  • Tsichlis PN, Bear SE. Infection by mink cell focus-forming viruses confers interleukin 2 (IL-2) independence to an IL-2-dependent rat T-cell lymphoma line. Proc Natl Acad Sci U S A. 1991 Jun 1;88(11):4611–4615. [PubMed]
  • Mann R, Mulligan RC, Baltimore D. Construction of a retrovirus packaging mutant and its use to produce helper-free defective retrovirus. Cell. 1983 May;33(1):153–159. [PubMed]
  • Miller AD, Buttimore C. Redesign of retrovirus packaging cell lines to avoid recombination leading to helper virus production. Mol Cell Biol. 1986 Aug;6(8):2895–2902. [PMC free article] [PubMed]
  • Danos O, Mulligan RC. Safe and efficient generation of recombinant retroviruses with amphotropic and ecotropic host ranges. Proc Natl Acad Sci U S A. 1988 Sep;85(17):6460–6464. [PubMed]
  • Markowitz D, Goff S, Bank A. A safe packaging line for gene transfer: separating viral genes on two different plasmids. J Virol. 1988 Apr;62(4):1120–1124. [PMC free article] [PubMed]
  • Muenchau DD, Freeman SM, Cornetta K, Zwiebel JA, Anderson WF. Analysis of retroviral packaging lines for generation of replication-competent virus. Virology. 1990 May;176(1):262–265. [PubMed]
  • Markowitz D, Goff S, Bank A. Construction and use of a safe and efficient amphotropic packaging cell line. Virology. 1988 Dec;167(2):400–406. [PubMed]
  • Cornetta K, Morgan RA, Gillio A, Sturm S, Baltrucki L, O'Reilly R, Anderson WF. No retroviremia or pathology in long-term follow-up of monkeys exposed to a murine amphotropic retrovirus. Hum Gene Ther. 1991 Fall;2(3):215–219. [PubMed]
  • Nienhuis AW, McDonagh KT, Bodine DM. Gene transfer into hematopoietic stem cells. Cancer. 1991 May 15;67(10 Suppl):2700–2704. [PubMed]
  • Karlsson S. Treatment of genetic defects in hematopoietic cell function by gene transfer. Blood. 1991 Nov 15;78(10):2481–2492. [PubMed]
  • Kantoff PW, Gillio AP, McLachlin JR, Bordignon C, Eglitis MA, Kernan NA, Moen RC, Kohn DB, Yu SF, Karson E, et al. Expression of human adenosine deaminase in nonhuman primates after retrovirus-mediated gene transfer. J Exp Med. 1987 Jul 1;166(1):219–234. [PMC free article] [PubMed]
  • Bodine DM, McDonagh KT, Brandt SJ, Ney PA, Agricola B, Byrne E, Nienhuis AW. Development of a high-titer retrovirus producer cell line capable of gene transfer into rhesus monkey hematopoietic stem cells. Proc Natl Acad Sci U S A. 1990 May;87(10):3738–3742. [PubMed]
  • Nienhuis AW, Donahue RE, Karlsson S, Clark SC, Agricola B, Antinoff N, Pierce JE, Turner P, Anderson WF, Nathan DG. Recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) shortens the period of neutropenia after autologous bone marrow transplantation in a primate model. J Clin Invest. 1987 Aug;80(2):573–577. [PMC free article] [PubMed]
  • Wieder R, Cornetta K, Kessler SW, Anderson WF. Increased efficiency of retroviral-mediated gene transfer and expression in primate bone marrow progenitors after 5-fluorouracil-induced hematopoietic suppression and recovery. Blood. 1991 Feb 1;77(3):448–455. [PubMed]
  • Martin FH, Suggs SV, Langley KE, Lu HS, Ting J, Okino KH, Morris CF, McNiece IK, Jacobsen FW, Mendiaz EA, et al. Primary structure and functional expression of rat and human stem cell factor DNAs. Cell. 1990 Oct 5;63(1):203–211. [PubMed]
  • Demetri GD, Griffin JD. Granulocyte colony-stimulating factor and its receptor. Blood. 1991 Dec 1;78(11):2791–2808. [PubMed]
  • Gasson JC. Molecular physiology of granulocyte-macrophage colony-stimulating factor. Blood. 1991 Mar 15;77(6):1131–1145. [PubMed]
  • Kirshenbaum AS, Goff JP, Kessler SW, Mican JM, Zsebo KM, Metcalfe DD. Effect of IL-3 and stem cell factor on the appearance of human basophils and mast cells from CD34+ pluripotent progenitor cells. J Immunol. 1992 Feb 1;148(3):772–777. [PubMed]
  • Kirshenbaum AS, Kessler SW, Goff JP, Metcalfe DD. Demonstration of the origin of human mast cells from CD34+ bone marrow progenitor cells. J Immunol. 1991 Mar 1;146(5):1410–1415. [PubMed]
  • Krantz SB. Erythropoietin. Blood. 1991 Feb 1;77(3):419–434. [PubMed]
  • Kishimoto T. The biology of interleukin-6. Blood. 1989 Jul;74(1):1–10. [PubMed]
  • Yang YC, Ciarletta AB, Temple PA, Chung MP, Kovacic S, Witek-Giannotti JS, Leary AC, Kriz R, Donahue RE, Wong GG, et al. Human IL-3 (multi-CSF): identification by expression cloning of a novel hematopoietic growth factor related to murine IL-3. Cell. 1986 Oct 10;47(1):3–10. [PubMed]
  • Evans LH, Morrison RP, Malik FG, Portis J, Britt WJ. A neutralizable epitope common to the envelope glycoproteins of ecotropic, polytropic, xenotropic, and amphotropic murine leukemia viruses. J Virol. 1990 Dec;64(12):6176–6183. [PMC free article] [PubMed]
  • Kadan MJ, Sturm S, Anderson WF, Eglitis MA. Detection of receptor-specific murine leukemia virus binding to cells by immunofluorescence analysis. J Virol. 1992 Apr;66(4):2281–2287. [PMC free article] [PubMed]
  • Bassin RH, Tuttle N, Fischinger PJ. Rapid cell culture assay technic for murine leukaemia viruses. Nature. 1971 Feb 19;229(5286):564–566. [PubMed]
  • Dezzutti CS, Lazo A, Yee JY, Blakeslee JR, Mathes LE, Brown BG, Lairmore MD. Detection of simian T-lymphotropic virus type I using the polymerase chain reaction. Int J Cancer. 1992 Mar 12;50(5):805–810. [PubMed]
  • Job G, Pfreundschuh M, Bauer M, zum Winkel K, Hunstein W. The influence of radiation therapy on T-lymphocyte subpopulations defined by monoclonal antibodies. Int J Radiat Oncol Biol Phys. 1984 Nov;10(11):2077–2081. [PubMed]
  • Daley JP, Rozans MK, Smith BR, Burakoff SJ, Rappeport JM, Miller RA. Retarded recovery of functional T cell frequencies in T cell-depleted bone marrow transplant recipients. Blood. 1987 Oct;70(4):960–964. [PubMed]
  • Shih A, Coutavas EE, Rush MG. Evolutionary implications of primate endogenous retroviruses. Virology. 1991 Jun;182(2):495–502. [PubMed]
  • Schuening FG, Kawahara K, Miller AD, To R, Goehle S, Stewart D, Mullally K, Fisher L, Graham TC, Appelbaum FR, et al. Retrovirus-mediated gene transduction into long-term repopulating marrow cells of dogs. Blood. 1991 Nov 15;78(10):2568–2576. [PubMed]
  • Carter RF, Abrams-Ogg AC, Dick JE, Kruth SA, Valli VE, Kamel-Reid S, Dubé ID. Autologous transplantation of canine long-term marrow culture cells genetically marked by retroviral vectors. Blood. 1992 Jan 15;79(2):356–364. [PubMed]
  • Moore KA, Deisseroth AB, Reading CL, Williams DE, Belmont JW. Stromal support enhances cell-free retroviral vector transduction of human bone marrow long-term culture-initiating cells. Blood. 1992 Mar 15;79(6):1393–1399. [PubMed]

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