title: TRIM5α variations influence transduction efficiency with lentiviral vectors in both human and rhesus CD34(+) cells in vitro and in vivo.
abstract: Human immunodeficiency virus type 1 (HIV-1) vectors can transduce human hematopoietic stem cells (HSC), but transduction efficiency varies among individuals. The innate immune factor tripartite motif-containing protein 5α (TRIM5α) plays an important role for restriction of retroviral infection. In this study, we examined whether TRIM5α could account for variations in transduction efficiency using both an established rhesus gene therapy model and human CD34(+) cell culture. Evaluation of TRIM5α genotypes (Mamu-1, -2, -3, -4, -5, and TrimCyp) in 16 rhesus macaques that were transplanted with transduced CD34(+) cells showed a significant correlation between TRIM5α Mamu-4 and high gene marking in both lymphocytes and granulocytes 6 months after transplantation. Since significant human TRIM5α coding polymorphisms were not known, we evaluated TRIM5α expression levels in human CD34(+) cells from 14 donors. Three days after HIV-1 vector transduction, measured transduction efficiency varied significantly among donors and was negatively correlated with TRIM5α expression levels. In summary, transduction efficiency in both rhesus and human CD34(+) cells was influenced by TRIM5α variations (genotypes and expression levels). Our findings are important for both understanding and mitigating the variability of transduction efficiency for rhesus and human CD34(+) cells.
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart Lung and Blood Institutes/National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Molly E
authors.initials: ME
authors.lastname: Evans
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart Lung and Blood Institutes/National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Chutima
authors.initials: C
authors.lastname: Kumkhaek
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart Lung and Blood Institutes/National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Hsieh
authors.affiliation: Hematology Branch, National Heart Lung and Blood Institutes, National Institutes of Health, Rockville, Maryland, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Donahue
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart Lung and Blood Institutes/National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: John F
authors.initials: JF
authors.lastname: Tisdale
authors.affiliation: Molecular and Clinical Hematology Branch, National Heart Lung and Blood Institutes/National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland, USA. Electronic address: uchidan@nhlbi.nih.gov.
authors.forename: Naoya
authors.initials: N
authors.lastname: Uchida
mesh_terms: D051997:ADP-ribosyl Cyclase 1 / Q000378:metabolism; D000483:Alleles; D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins / Q000235:genetics*; D002460:Cell Line; D015870:Gene Expression; D005787:Gene Frequency; D014644:Genetic Variation; D005822:Genetic Vectors / Q000235:genetics*; D005838:Genotype; D006098:Granulocytes / Q000378:metabolism; D015497:HIV-1 / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D016086:Lentivirus / Q000235:genetics*; D008253:Macaca mulatta; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D034622:RNA Interference; D015302:Simian Immunodeficiency Virus / Q000235:genetics; D013601:T-Lymphocytes / Q000378:metabolism; D014158:Transcription, Genetic; D014161:Transduction, Genetic; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases
chemical_list: D018952:Antigens, CD34; D000090103:Antiviral Restriction Factors; D002352:Carrier Proteins; D000070584:Tripartite Motif Proteins; C477346:TRIM5 protein, human; D044767:Ubiquitin-Protein Ligases; D051997:ADP-ribosyl Cyclase 1