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 | Zendy

Guohua Yi | Zendy; Jang Gi Choi | Zendy; Preeti Bharaj | Zendy; Sojan Abraham | Zendy; Ying Dang | Zendy; Tal Kafri | Zendy; Ogechika Alozie | Zendy; Manjunath N Manjunath | Zendy; Premlata Shankar | Zendy

Open Access

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

Author(s) -

Guohua Yi,

Jang Gi Choi,

Preeti Bharaj,

Sojan Abraham,

Ying Dang,

Tal Kafri,

Ogechika Alozie,

Manjunath N Manjunath,

Premlata Shankar

Publication year - 2014

Publication title -

molecular therapy — nucleic acids

Language(s) - English

Resource type - Journals

SCImago Journal Rank - 2.208

H-Index - 59

ISSN - 2162-2531

DOI - 10.1038/mtna.2014.52

Subject(s) - virology , genetic enhancement , zinc finger nuclease , biology , lentivirus , virus , viral vector , genome editing , gene , crispr , viral disease , genetics , recombinant dna

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

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