Development of a human immunodeficiency virus type 1-based lentiviral vector that allows efficient transduction of both human and rhesus blood cells.
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.
Uchida
Naoya
N
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.
Washington
Kareem N
KN
Hayakawa
Jun
J
Hsieh
Matthew M
MM
Bonifacino
Aylin C
AC
Krouse
Allen E
AE
Metzger
Mark E
ME
Donahue
Robert E
RE
Tisdale
John F
JF
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
D018952:Antigens, CD34