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Journal of Virology, October 2009, p. 9854-9862, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.00357-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Development of a Human Immunodeficiency Virus Type 1-Based Lentiviral Vector That Allows Efficient Transduction of both Human and Rhesus Blood Cells{triangledown} ,{dagger}

Naoya Uchida,1,2,3 Kareem N. Washington,1 Jun Hayakawa,1 Matthew M. Hsieh,1 Aylin C. Bonifacino,4 Allen E. Krouse,4 Mark E. Metzger,4 Robert E. Donahue,4 and John F. Tisdale1*

Molecular and Clinical Hematology Branch, National Heart, Lung, and Blood Institute (NHLBI)/National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health (NIH), Bethesda, Maryland,1 Division of Hematology, Department of Internal Medicine, Nippon Medical School (NMS), Tokyo, Japan,2 Molecular Genetics, NMS, Tokyo, Japan,3 Hematology Branch, NHLBI, NIH, 5 Research Court, Rockville, Maryland4

Received 17 February 2009/ Accepted 16 July 2009

Human immunodeficiency virus type 1 (HIV-1) vectors transduce rhesus blood cells poorly due to a species-specific block by TRIM5{alpha} 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 ({chi}HIV) 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 {chi}HIV and HIV-1 vectors showed similar transduction efficiencies; in rhesus CD34+ HSCs, the {chi}HIV vector yielded superior transduction rates. In in vivo competitive repopulation experiments with two rhesus macaques, the {chi}HIV 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.

* Corresponding author. Mailing address: Molecular and Clinical Hematology Branch, 9000 Rockville Pike, Bldg. 10, 9N116, Bethesda, Maryland 20892. Phone: (301) 402-6497. Fax: (301) 480-8975. E-mail: johntis{at}nhlbi.nih.gov

{triangledown} Published ahead of print on 22 July 2009.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, October 2009, p. 9854-9862, Vol. 83, No. 19
0022-538X/09/$08.00+0     doi:10.1128/JVI.00357-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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