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Gene transfer of two entry inhibitors protects CD4+ T cell from HIV-1 infection in humanized mice

Gene Therapy volume 23, pages 144–150 (2016)Cite this article

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Abstract

Targeting viral entry is the most likely gene therapy strategy to succeed in protecting the immune system from pathogenic HIV-1 infection. Here, we evaluated the efficacy of a gene transfer lentiviral vector expressing a combination of viral entry inhibitors, the C46 peptide (an inhibitor of viral fusion) and the P2-CCL5 intrakine (a modulator of CCR5 expression), to prevent CD4+ T-cell infection in vivo. For this, we used two different models of HIV-1-infected mice, one in which ex vivo genetically modified human T cells were grafted into immunodeficient NOD.SCID.γc−/− mice before infection and one in which genetically modified T cells were derived from CD34+ hematopoietic progenitors grafted few days after birth. Expression of the transgenes conferred a major selective advantage to genetically modified CD4+ T cells, the frequency of which could increase from 10 to 90% in the blood following HIV-1 infection. Moreover, these cells resisted HIV-1-induced depletion, contrary to non-modified cells that were depleted in the same mice. Finally, we report lower normalized viral loads in mice having received genetically modified progenitors. Altogether, our study documents that targeting viral entry in vivo is a promising avenue for the future of HIV-1 gene therapy in humans.

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Acknowledgements

This work was supported by grants from Agence Nationale de la Recherche contre le SIDA (ANRS) to Guy Gorochov and Gilles Marodon. NYP was supported by a doctoral fellowship from Fond Pierre Bergé/SIDAction and by the ANRS. We thank David Klatzmann (INSERM U959, Paris, France) for his initial support on this project, Dorothée van Laer (Innsbruck University, Austria) for the kind gift of the C46 peptide, Arnaud Moris (CIMI-PARIS, France) for the kind gift of NL-AD8 HIV-1 strain, Dr Hans Yssel (CIMI-PARIS) for performing Hoechst-based detection test of mycoplasma.

Author contributions

NYP, CB, AB and GM performed experiments; BL constructed the vectors; CA and VS performed HIV-1 qPCR; KD, FML and GG conceived experiments, contributed to essential reagents and corrected the manuscript; NYP and GM conceived experiments, analyzed the data and wrote the manuscript.

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Authors and Affiliations

  1. Sorbonne Universités, UPMC Univ PARIS 06, CR7, INSERM U1135, CNRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Paris, France

    N Y Petit, C Baillou, A Burlion, K Dorgham, C Amiel, F M Lemoine, G Gorochov & G Marodon

  2. Sorbonne Universités, UPMC Univ PARIS 06, CR7, INSERM U959, Paris, France

    B Levacher

  3. AP-HP, Hôpital Tenon, Service de Virologie, Paris, France

    C Amiel & V Schneider

  4. Département d'Immunologie, AP-HP, Hôpital Pitié-Salpêtrière, Paris, France

    G Gorochov

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  1. N Y Petit
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  2. C Baillou
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  3. A Burlion
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  4. K Dorgham
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  8. F M Lemoine
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  9. G Gorochov
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Correspondence to G Marodon.

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Petit, N., Baillou, C., Burlion, A. et al. Gene transfer of two entry inhibitors protects CD4+ T cell from HIV-1 infection in humanized mice. Gene Ther 23, 144–150 (2016). https://doi.org/10.1038/gt.2015.101

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