Control of HIV Infection In Vivo Using Gene Therapy with a Secreted Entry Inhibitor

Molecular Therapy: Nucleic Acids

Juan Carlos Zúñiga-Pflücker¹  Jastaranpreet Singh¹  Danila Leontyev²  Alexander Falkenhagen²  Stanley Read²  Sadhna Joshi²  Sabah Asad³ 

[1] Department of Immunology, University of Toronto, Toronto, ON, Canada;Department of Molecular Genetics, University of Toronto, Toronto, ON M5S 3E2, Canada;Department of Pediatrics, The Hospital for Sick Children, Toronto, ON, Canada;

关键词: HIV;    gene therapy;    NSG mouse model;    entry inhibitor;    soluble CD4;    hematopoietic stem cells;    T cells;    HIV entry;    promoter;    humanized mice;   

DOI  :  10.1016/j.omtn.2017.08.017

来源: DOAJ

【 摘 要 】

HIV entry inhibitors are highly effective in controlling virus replication. We have developed a lentiviral vector that expresses a secreted entry inhibitor, soluble CD4 (sCD4), which binds to the HIV envelope glycoproteins and inactivates the virus. We have shown that sCD4 was secreted from gene-modified CD4+ T cells, as well as from human umbilical cord blood-derived CD34+ hematopoietic stem/progenitor cells (HSPCs), and protected unmodified HIV target cells from infection in vitro. To investigate the in vivo application of our approach, we injected gene-modified HSPCs into NOD/SCID/γcnull (NSG) mice. NSG hosts supported multi-lineage differentiation of human gene-modified HSPCs. Upon challenge with HIV, humanized mice capable of secreting sCD4 demonstrated a reduction of viral load over time compared to control humanized mice. In contrast to gene therapy approaches that render only gene-modified HIV target cells resistant to infection, our approach also showed protection of unmodified CD4+ T cells in the peripheral blood and tissues. Our findings provide support for the continuous delivery of secreted entry inhibitors via gene therapy as an alternative to oral administration of antiretroviral drugs or injection of antiretroviral proteins, including antibodies.

【 授权许可】

Unknown