title: Gene transfer properties and structural modeling of human stem cell-derived AAV.
abstract: Adeno-associated virus (AAV) vectors are proving to be remarkably successful for in vivo gene delivery. Based upon reports of abundant AAV in the human marrow, we tested CD34(+) hematopoietic stem cells for the presence of natural AAV. Here, we report for the first time, the presence of novel AAV variants in healthy CD34(+) human peripheral blood stem cells. The majority of healthy peripheral blood stem cell donors were found to harbor AAV in their CD34(+) cells. Every AAV isolated from CD34(+) cells mapped to AAV Clade F. Gene transfer vectors derived from these novel AAVs efficiently underwent entry and postentry processing in human cord blood stem cells and supported stable gene transfer into long-term, in vivo engrafting human HSCs significantly better than other serotypes. AAVHSC-transduced human CD34(+) cells engrafted in vivo and gave rise to differentiated transgene-expressing progeny. Importantly, gene-marked CD34(+) stem cells persisted long term in xenograft recipients, indicating transduction of primitive progenitors. Notably, correlation of structure with function permitted identification of potential capsid components important for HSC transduction. Thus, AAVHSCs represent a new class of genetic vectors for the manipulation of HSC genomes.
authors.affiliation: AAV Laboratory, Department of Virology, Beckman Research Institute of City of Hope, Duarte, California, USA.
authors.forename: Laura J
authors.initials: LJ
authors.lastname: Smith
authors.affiliation: AAV Laboratory, Department of Virology, Beckman Research Institute of City of Hope, Duarte, California, USA.
authors.forename: Taihra
authors.initials: T
authors.lastname: Ul-Hasan
authors.affiliation: AAV Laboratory, Department of Virology, Beckman Research Institute of City of Hope, Duarte, California, USA.
authors.forename: Sarah K
authors.initials: SK
authors.lastname: Carvaines
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Structural Biology, The McKnight Brain Institute University of Florida, Gainesville, Florida, USA.
authors.forename: Kim
authors.initials: K
authors.lastname: Van Vliet
authors.affiliation: AAV Laboratory, Department of Virology, Beckman Research Institute of City of Hope, Duarte, California, USA.
authors.forename: Ethel
authors.initials: E
authors.lastname: Yang
authors.affiliation: Divisions of Hematology/Stem Cell Transplantation, Beckman Research Institute of City of Hope, Duarte, California, USA.
authors.forename: Kamehameha K
authors.initials: KK
authors.lastname: Wong
authors.affiliation: Department of Biochemistry and Molecular Biology, Center for Structural Biology, The McKnight Brain Institute University of Florida, Gainesville, Florida, USA.
authors.forename: Mavis
authors.initials: M
authors.lastname: Agbandje-McKenna
authors.affiliation: AAV Laboratory, Department of Virology, Beckman Research Institute of City of Hope, Duarte, California, USA.
authors.forename: Saswati
authors.initials: S
authors.lastname: Chatterjee
mesh_terms: D000818:Animals; D018952:Antigens, CD34 / Q000378:metabolism*; D036022:Capsid Proteins / Q000378:metabolism; D002478:Cells, Cultured; D000229:Dependovirus / Q000502:physiology*; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000276:immunology / Q000378:metabolism* / Q000821:virology*; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008954:Models, Biological; D010802:Phylogeny; D014161:Transduction, Genetic
chemical_list: D018952:Antigens, CD34; D036022:Capsid Proteins