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Blood, 28 May 2009, Vol. 113, No. 22, pp. 5434-5443.
Prepublished online as a Blood First Edition Paper on April 1, 2009; DOI 10.1182/blood-2008-10-185199.
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Submitted October 21, 2008
Accepted March 9, 2009
Sustained high level polyclonal hematopoietic marking and transgene expression four years following autologous transplantation of rhesus macaques with SIV lentiviral vector transduced CD34+ cells
Yoo-Jin Kim, Yoon-Sang Kim, Andre Larochelle, Gabriel Renaud, Tyra G. Wolfsberg, Rima Adler, Robert E. Donahue, Peiman Hematti, Bum-Kee Hong, Jean Roayaei, Keiko Akagi, Janice M. Riberdy, Arthur W. Nienhuis, Cynthia E. Dunbar*, and Derek A. Persons
Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD, United States
Department of Hematology, St. Jude Children's Research Hospital, Memphis, TN, United States
Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD, United States
Mouse Cancer Genetics Program, Center for Cancer Research, National Cancer Institute, Frederick, MD, United States
Department of Immunology, St. Jude Children's Research Hospital, Memphis, TN, United States
* Corresponding author; email: dunbarc{at}nhlbi.nih.gov.
We previously reported that lentiviral vectors derived from the simian immunodeficiency virus (SIV) were efficient at transducing rhesus hematopoietic repopulating cells. To evaluate the persistence of vector-containing and expressing cells long-term, and the safety implications of SIV lentiviral vector-mediated gene transfer, we followed three rhesus macaques for more than four years following transplantation with transduced CD34+ cells. All three animals demonstrated significant vector marking and expression of the GFP transgene in T cells, B cells and granulocytes, with mean GFP + levels of 6.7% (range, 3.3-13.0%), 7.4% (4.2-13.4%) and 5.6% (3.1-10.5%) respectively. There was no vector silencing in hematopoietic cells over time. Vector insertion site analysis of granulocytes demonstrated sustained highly polyclonal reconstitution, with no evidence for progression to oligoclonality. A significant number of clones were found to contribute at both one year and three or four year time points. No vector integrations were detected in the MDS1/EVI1 region, in contrast to our previous findings with a  -retroviral vector. These data show that lentiviral vectors can mediate stable and efficient long-term expression in the progeny of transduced hematopoietic stem cells, with an integration profile that may be safer than that of standard MLV-derived retroviral vectors.
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[Abstract]
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