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

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

doi:10.1038/mtna.2014.52

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

Guohua Yi, Jang Gi Choi, Preeti Bharaj, Sojan Abraham, Ying Dang, Tal Kafri, Ogechika Alozie, Manjunath N. Manjunath, Premlata Shankar

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

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.

Original language	English (US)
Article number	e198
Journal	Molecular Therapy Nucleic Acids
Volume	3
DOIs	https://doi.org/10.1038/mtna.2014.52
State	Published - Sep 30 2014
Externally published	Yes

Keywords

CCR5 gene editing
HIV-1 therapy
humanized mice
non-integrating lentivirus
resting CD4+ T cells
zinc finger nucleases

ASJC Scopus subject areas

Molecular Medicine
Drug Discovery

Access to Document

10.1038/mtna.2014.52

Cite this

Yi, G., Choi, J. G., Bharaj, P., Abraham, S., Dang, Y., Kafri, T., Alozie, O., Manjunath, M. N., & Shankar, P. (2014). 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. Molecular Therapy Nucleic Acids, 3, Article e198. https://doi.org/10.1038/mtna.2014.52

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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 na{\"i}ve 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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