期刊
MOLECULAR THERAPY-NUCLEIC ACIDS
卷 3, 期 -, 页码 -出版社
CELL PRESS
DOI: 10.1038/mtna.2014.52
关键词
CCR5 gene editing; HIV-1 therapy; humanized mice; non-integrating lentivirus; resting CD4(+) T cells; zinc finger nucleases
资金
- NIH/NHLBI [R21HL116268]
- NIH/NIAID [RO1 AI071882, R01-DK058702-10]
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 IL2r gamma c null (NSG) mice. Likewise, endogenous virus replication was suppressed in NSG mice reconstituted with CCR5-ZFN-transduced resting CD4(+) T cells from treatment naive 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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