title: Sustained high-level polyclonal hematopoietic marking and transgene expression 4 years after autologous transplantation of rhesus macaques with SIV lentiviral vector-transduced CD34+ cells.
abstract: 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 3 rhesus macaques for more than 4 years after transplantation with transduced CD34+ cells. All 3 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 1-year and 3- or 4-year time points. No vector integrations were detected in the MDS1/EVI1 region, in contrast to our previous findings with a gamma-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 Moloney murine leukemia virus (MLV)-derived retroviral vectors.
authors.affiliation: Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, MD 20852, USA.
authors.forename: Yoo-Jin
authors.initials: YJ
authors.lastname: Kim
authors.forename: Yoon-Sang
authors.initials: YS
authors.lastname: Kim
authors.forename: Andre
authors.initials: A
authors.lastname: Larochelle
authors.forename: Gabriel
authors.initials: G
authors.lastname: Renaud
authors.forename: Tyra G
authors.initials: TG
authors.lastname: Wolfsberg
authors.forename: Rima
authors.initials: R
authors.lastname: Adler
authors.forename: Robert E
authors.initials: RE
authors.lastname: Donahue
authors.forename: Peiman
authors.initials: P
authors.lastname: Hematti
authors.forename: Bum-Kee
authors.initials: BK
authors.lastname: Hong
authors.forename: Jean
authors.initials: J
authors.lastname: Roayaei
authors.forename: Keiko
authors.initials: K
authors.lastname: Akagi
authors.forename: Janice M
authors.initials: JM
authors.lastname: Riberdy
authors.forename: Arthur W
authors.initials: AW
authors.lastname: Nienhuis
authors.forename: Cynthia E
authors.initials: CE
authors.lastname: Dunbar
authors.forename: Derek A
authors.initials: DA
authors.lastname: Persons