Cargando…

Preclinical Development and Clinical-Scale Manufacturing of HIV Gag-Specific, LentivirusModified CD4 T Cells for HIV Functional Cure

Activation, infection, and eventual depletion of human immunodeficiency virus (HIV)-specific cluster of differentiation 4 (CD4) T cells are the crucial pathogenetic events in acquired immunodeficiency syndrome (AIDS). We developed a cell and gene therapy to reconstitute HIV-specific CD4 T cells and...

Descripción completa

Detalles Bibliográficos
Autores principales: Li, Haishan, Lahusen, Tyler, Xiao, Lingzhi, Muvarak, Nidal, Blazkova, Jana, Chun, Tae-Wook, Pauza, C. David
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society of Gene & Cell Therapy 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7240062/
https://www.ncbi.nlm.nih.gov/pubmed/32462053
http://dx.doi.org/10.1016/j.omtm.2020.04.024
Descripción
Sumario:Activation, infection, and eventual depletion of human immunodeficiency virus (HIV)-specific cluster of differentiation 4 (CD4) T cells are the crucial pathogenetic events in acquired immunodeficiency syndrome (AIDS). We developed a cell and gene therapy to reconstitute HIV-specific CD4 T cells and prevent their destruction by HIV. Antigen-specific CD4 T cells will provide helper functions to support antiviral cytotoxic T lymphocyte (CTL) function and the production of virus-specific antibodies. However, ex vivo expansion of HIV-specific CD4 T cells is poor and previous gene therapies focused on bulk CD4 T cells without enriching for an antigen-specific subset. We developed a method for manufacturing autologous CD4(+) T cell products highly enriched with Gag-specific T cells. Rare Gag-specific CD4 T cells in peripheral blood mononuclear cells (PBMCs) were increased nearly 1,000-fold by stimulating PBMC with Gag peptides, followed by depleting nontarget cells and transducing with lentivirus vector AGT103 to protect against HIV-mediated depletion and inhibit HIV release from latently infected cells. The average percentage of HIV-specific CD4 cells in the final products was 15.13%, and the average yield was 7 × 10(8) cells. The protocol for clinical-scale manufacturing of HIV-specific and HIV-resistant CD4 T cells is an important step toward effective immunotherapy for HIV disease.