title: Development of a human immunodeficiency virus type 1-based lentiviral vector that allows efficient transduction of both human and rhesus blood cells.
abstract: Human immunodeficiency virus type 1 (HIV-1) vectors transduce rhesus blood cells poorly due to a species-specific block by TRIM5alpha and APOBEC3G, which target HIV-1 capsid and viral infectivity factor (Vif), respectively. We sought to develop a lentiviral vector capable of transducing both human and rhesus blood cells by combining components of both HIV-1 and simian immunodeficiency virus (SIV), including SIV capsid (sCA) and SIV Vif. A chimeric HIV-1 vector including sCA (chiHIV) was superior to the conventional SIV in transducing a human blood cell line and superior to the conventional HIV-1 vector in transducing a rhesus blood cell line. Among human CD34(+) hematopoietic stem cells (HSCs), the chiHIV and HIV-1 vectors showed similar transduction efficiencies; in rhesus CD34(+) HSCs, the chiHIV vector yielded superior transduction rates. In in vivo competitive repopulation experiments with two rhesus macaques, the chiHIV vector demonstrated superior marking levels over the conventional HIV-1 vector in all blood lineages (first rhesus, 15 to 30% versus 1 to 5%; second rhesus, 7 to 15% versus 0.5 to 2%, respectively) 3 to 7 months postinfusion. In summary, we have developed an HIV-1-based lentiviral vector system that should allow comprehensive preclinical testing of HIV-1-based therapeutic vectors in the rhesus macaque model with eventual clinical application.
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute/National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Naoya
authors.initials: N
authors.lastname: Uchida
authors.forename: Kareem N
authors.initials: KN
authors.lastname: Washington
authors.forename: Jun
authors.initials: J
authors.lastname: Hayakawa
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hsieh
authors.forename: Aylin C
authors.initials: AC
authors.lastname: Bonifacino
authors.forename: Allen E
authors.initials: AE
authors.lastname: Krouse
authors.forename: Mark E
authors.initials: ME
authors.lastname: Metzger
authors.forename: Robert E
authors.initials: RE
authors.lastname: Donahue
authors.forename: John F
authors.initials: JF
authors.lastname: Tisdale
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000096:biosynthesis; D002213:Capsid / Q000378:metabolism; D002460:Cell Line; D004912:Erythrocytes / Q000821:virology; D005822:Genetic Vectors / Q000235:genetics*; D015497:HIV-1 / Q000378:metabolism*; D006412:Hematopoietic Stem Cells / Q000821:virology; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008253:Macaca mulatta; D008957:Models, Genetic; D009154:Mutation; D015302:Simian Immunodeficiency Virus / Q000378:metabolism*; D014161:Transduction, Genetic
chemical_list: D018952:Antigens, CD34