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 journalArticle

25 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 languageEnglish (US)
Article numbere198
JournalMolecular Therapy - Nucleic Acids
Volume3
DOIs
StatePublished - Sep 30 2014

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

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