High-efficiency Transduction of Rhesus Hematopoietic Repopulating Cells by a Modified HIV1-based Lentiviral Vector

作者：Uchida Naoya; Hargrove Phillip W; Lap Coen J; Evans Molly E; Phang Oswald; Bonifacino Aylin C; Krouse Allen E; Metzger Mark E; Anh Dao Nguyen; Hsieh Matthew M; Wolf**erg Tyra G; Donahue Robert E; Persons Derek A; Tisdale John F^*

来源：Molecular Therapy, 2012, 20(10): 1882-1892.

DOI：10.1038/mt.2012.159

Human immunodeficiency virus type 1 (HIV1) vectors poorly transduce rhesus hematopoietic cells due to species-specific restriction factors, including the tripartite motif-containing 5 isoform alpha (TRIM5 alpha) which targets the HIV1 capsid. We previously developed a chimeric HIV1 (chi HIV) vector system wherein the vector genome is packaged with the simian immunodeficiency virus (SIV) capsid for efficient transduction of both rhesus and human CD34(+) cells. To evaluate whether chi HIV vectors could efficiently transduce rhesus hematopoietic repopulating cells, we performed a competitive repopulation assay in rhesus macaques, in which half of the CD34(+) cells were transduced with standard SIV vectors and the other half with chi HIV vectors. As compared with SIV vectors, chi HIV vectors achieved higher vector integration, and the transgene expression rates were two- to threefold higher in granulocytes and red blood cells and equivalent in lymphocytes and platelets for 2 years. A recipient of chi HIV vector-only transduced cells reached up to 40% of transgene expression rates in granulocytes and lymphocytes and 20% in red blood cells. Similar to HIV1 and SIV vectors, chi HIV vector frequently integrated into gene regions, especially into introns. In summary, our chi HIV vector demonstrated efficient transduction for rhesus long-term repopulating cells, comparable with SIV vectors. This chi HIV vector should allow preclinical testing of HIV1-based therapeutic vectors in large animal models.

• 出版日期2012-10