title: Safety and efficacy of a tCD25 preselective combination anti-HIV lentiviral vector in human hematopoietic stem and progenitor cells.
abstract: The successful suppression of human immunodeficiency virus (HIV) in the "Berlin Patient" has highlighted the ability of HIV-resistant hematopoietic stem cells to offer a potential functional cure for HIV-infected patients. HIV stem cell gene therapy can mimic this result by genetically modifying a patient's own cells with anti-HIV genes. Previous attempts of HIV gene therapy have been hampered by a low percentage of transplanted HIV-resistant cells which has led to minimal clinical efficacy. In our current study, we have evaluated the in vitro and in vivo safety and efficacy of a truncated/mutated form of human CD25 preselective anti-HIV lentiviral vector in human hematopoietic stem cells. This preselective vector allows us to purify vector-transduced cells prior to transplantation so an increased percentage of gene-modified cells can be delivered. Here, we demonstrate the safety of this strategy with successful engraftment and multilineage hematopoiesis of transduced cells in a humanized NOD-RAG1-/-IL-2rγ-/- knockout mouse model. Efficacy was also demonstrated with significant protection from HIV-1 infection including maintenance of human CD4+ cell levels and a decrease in HIV-1 plasma viremia. Collectively, these results establish the utility of this HIV stem cell gene therapy strategy and bring it closer to providing a functional cure for HIV-infected patients.
authors.affiliation: Department of Internal Medicine, University of California Davis, Sacramento, California, USA.
authors.forename: Sharlie L
authors.initials: SL
authors.lastname: Barclay
authors.forename: Yimin
authors.initials: Y
authors.lastname: Yang
authors.forename: Siruo
authors.initials: S
authors.lastname: Zhang
authors.forename: Ryan
authors.initials: R
authors.lastname: Fong
authors.forename: Alfonso
authors.initials: A
authors.lastname: Barraza
authors.forename: Jan A
authors.initials: JA
authors.lastname: Nolta
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Torbett
authors.forename: Mehrdad
authors.initials: M
authors.lastname: Abedi
authors.forename: Gerhard
authors.initials: G
authors.lastname: Bauer
authors.forename: Joseph S
authors.initials: JS
authors.lastname: Anderson
mesh_terms: D000818:Animals; D015870:Gene Expression; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000276:immunology / Q000502:physiology*; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D014161:Transduction, Genetic / Q000379:methods
chemical_list: C508017:IL2RA protein, human; D053645:Interleukin-2 Receptor alpha Subunit
keywords: Gene therapy; Hematopoietic cells; Human immunodeficiency virus; Lentiviral vector