title: CCR5 Gene Editing of Resting CD4(+) T Cells by Transient ZFN Expression From HIV Envelope Pseudotyped Nonintegrating Lentivirus Confers HIV-1 Resistance in Humanized Mice.
abstract: CCR5 disruption by zinc finger nucleases (ZFNs) is a promising method for HIV-1 gene therapy. However, successful clinical translation of this strategy necessitates the development of a safe and effective method for delivery into relevant cells. We used non-integrating lentivirus (NILV) for transient expression of ZFNs and pseudotyped the virus with HIV-envelope for targeted delivery to CD4(+) T cells. Both activated and resting primary CD4(+) T cells transduced with CCR5-ZFNs NILV showed resistance to HIV-1 infection in vitro. Furthermore, NILV transduced resting CD4(+) T cells from HIV-1 seronegative individuals were resistant to HIV-1 challenge when reconstituted into NOD-scid IL2rγc null (NSG) mice. Likewise, endogenous virus replication was suppressed in NSG mice reconstituted with CCR5-ZFN-transduced resting CD4(+) T cells from treatment naïve as well as ART-treated HIV-1 seropositive patients. Taken together, NILV pseudotyped with HIV envelope provides a simple and clinically viable strategy for HIV-1 gene therapy.
authors.affiliation: Department of Biomedical Sciences, Center of Excellence for Infectious Diseases, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Guohua
authors.initials: G
authors.lastname: Yi
authors.affiliation: Department of Biomedical Sciences, Center of Excellence for Infectious Diseases, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Jang Gi
authors.initials: JG
authors.lastname: Choi
authors.affiliation: Department of Biomedical Sciences, Center of Excellence for Infectious Diseases, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Preeti
authors.initials: P
authors.lastname: Bharaj
authors.affiliation: Department of Biomedical Sciences, Center of Excellence for Infectious Diseases, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Sojan
authors.initials: S
authors.lastname: Abraham
authors.affiliation: Department of Biomedical Sciences, Center of Excellence for Infectious Diseases, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Dang
authors.affiliation: Department of Microbiology & Immunology, Gene Therapy Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Tal
authors.initials: T
authors.lastname: Kafri
authors.affiliation: Department of Internal Medicine, Paul L Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Ogechika
authors.initials: O
authors.lastname: Alozie
authors.affiliation: Department of Biomedical Sciences, Center of Excellence for Infectious Diseases, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Manjunath N
authors.initials: MN
authors.lastname: Manjunath
authors.affiliation: Department of Biomedical Sciences, Center of Excellence for Infectious Diseases, Paul L. Foster School of Medicine, Texas Tech University Health Sciences Center, El Paso, Texas, USA.
authors.forename: Premlata
authors.initials: P
authors.lastname: Shankar