Gene transfer of two entry inhibitors protects CD4⁺ T cell from HIV-1 infection in humanized mice.
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.
Sorbonne Universités, UPMC Univ PARIS 06, CR7, INSERM U1135, CNRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Paris, France.
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Petit
Sorbonne Universités, UPMC Univ PARIS 06, CR7, INSERM U1135, CNRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Paris, France.
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Baillou
Sorbonne Universités, UPMC Univ PARIS 06, CR7, INSERM U1135, CNRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Paris, France.
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Burlion
Sorbonne Universités, UPMC Univ PARIS 06, CR7, INSERM U1135, CNRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Paris, France.
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Dorgham
Sorbonne Universités, UPMC Univ PARIS 06, CR7, INSERM U959, Paris, France.
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Levacher
Sorbonne Universités, UPMC Univ PARIS 06, CR7, INSERM U1135, CNRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Paris, France.|AP-HP, Hôpital Tenon, Service de Virologie, Paris, France.
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Amiel
AP-HP, Hôpital Tenon, Service de Virologie, Paris, France.
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Schneider
Sorbonne Universités, UPMC Univ PARIS 06, CR7, INSERM U1135, CNRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Paris, France.
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Lemoine
Sorbonne Universités, UPMC Univ PARIS 06, CR7, INSERM U1135, CNRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Paris, France.|AP-HP, Hôpital Pitié-Salpêtrière, Département d'Immunologie, Paris, France.
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Gorochov
Sorbonne Universités, UPMC Univ PARIS 06, CR7, INSERM U1135, CNRS, Centre d'Immunologie et des Maladies Infectieuses (CIMI), Paris, France.
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http://orcid.org/0000-0003-4889-6785
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Marodon
D000818:Animals; D018952:Antigens, CD34; D065100:CCR5 Receptor Antagonists / Q000627:therapeutic use; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology / Q000637:transplantation / Q000821:virology*; D018946:Chemokine CCL5 / Q000235:genetics*; D005260:Female; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D015658:HIV Infections / Q000517:prevention & control*; D015497:HIV-1; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D019713:Receptors, CCR5 / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D053586:Virus Internalization
D018952:Antigens, CD34; C515020:C46 HIV-1 fusion inhibitory peptide; D065100:CCR5 Receptor Antagonists; D018946:Chemokine CCL5; D019713:Receptors, CCR5; D011993:Recombinant Fusion Proteins