title: Expression of chimeric receptor CD4ζ by natural killer cells derived from human pluripotent stem cells improves in vitro activity but does not enhance suppression of HIV infection in vivo.
abstract: Cell-based immunotherapy has been gaining interest as an improved means to treat human immunodeficiency virus (HIV)/AIDS. Human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs) could become a potential resource. Our previous studies have shown hESC and iPSC-derived natural killer (NK) cells can inhibit HIV-infected targets in vitro. Here, we advance those studies by expressing a HIV chimeric receptor combining the extracellular portion of CD4 to the CD3ζ intracellular signaling chain. We hypothesized that expression of this CD4ζ receptor would more efficiently direct hESC- and iPSC-derived NK cells to target HIV-infected cells. In vitro studies showed the CD4ζ expressing hESC- and iPSC-NK cells inhibited HIV replication in CD4+ T-cells more efficiently than their unmodified counterparts. We then evaluated CD4ζ expressing hESC (CD4ζ-hESC)- and iPSC-NK cells in vivo anti-HIV activity using a humanized mouse model. We demonstrated significant suppression of HIV replication in mice treated with both CD4ζ-modified and -unmodified hESC-/iPSC-NK cells compared with control mice. However, we did not observe significantly increased efficacy of CD4ζ expression in suppression of HIV infection. These studies indicate that hESC/iPSC-based immunotherapy can be used as a unique resource to target HIV/AIDS.
authors.affiliation: Department of Medicine, Stem Cell Institute, University of Minnesota, Minneapolis, Minnesota, USA.
authors.forename: Zhenya
authors.initials: Z
authors.lastname: Ni
authors.forename: David A
authors.initials: DA
authors.lastname: Knorr
authors.forename: Laura
authors.initials: L
authors.lastname: Bendzick
authors.forename: Jeremy
authors.initials: J
authors.lastname: Allred
authors.forename: Dan S
authors.initials: DS
authors.lastname: Kaufman
mesh_terms: D000818:Animals; D015704:CD4 Antigens / Q000096:biosynthesis* / Q000235:genetics; D002460:Cell Line; D053595:Embryonic Stem Cells / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D015658:HIV Infections / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D015497:HIV-1; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism* / Q000473:pathology; D007694:Killer Cells, Natural / Q000378:metabolism*; D051379:Mice; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000235:genetics; D033581:Stem Cell Transplantation
chemical_list: D015704:CD4 Antigens; D011993:Recombinant Fusion Proteins
keywords: HIV-1 infection inhibition; Human embryonic stem cells; In vitro; In vivo; Induced pluripotent stem cells; Natural killer cells