Engineering Cellular Resistance to HIV-1 Infection In Vivo Using a Dual Therapeutic Lentiviral Vector

• Main Authors: Bryan P Burke (Author), Bernard R Levin (Author), Jane Zhang (Author), Anna Sahakyan (Author), Joshua Boyer (Author), Maria V Carroll (Author), Joanna Camba Colón (Author), Naomi Keech (Author), Valerie Rezek (Author), Gregory Bristol (Author), Erica Eggers (Author), Ruth Cortado (Author), Maureen P Boyd (Author), Helen Impey (Author), Saki Shimizu (Author), Emily L Lowe (Author), Gene-Errol E Ringpis (Author), Sohn G Kim (Author), Dimitrios N Vatakis (Author), Louis R Breton (Author), Jeffrey S Bartlett (Author), Irvin S Y Chen (Author), Scott G Kitchen (Author), Dong Sung An (Author), Geoff P Symonds (Author)
• Format: Book
• Published: Elsevier, 2015-01-01T00:00:00Z.
• Subjects: article
• Online Access: Connect to this object online.

Summary

We described earlier a dual-combination anti-HIV type 1 (HIV-1) lentiviral vector (LVsh5/C46) that downregulates CCR5 expression of transduced cells via RNAi and inhibits HIV-1 fusion via cell surface expression of cell membrane-anchored C46 antiviral peptide. This combinatorial approach has two points of inhibition for R5-tropic HIV-1 and is also active against X4-tropic HIV-1. Here, we utilize the humanized bone marrow, liver, thymus (BLT) mouse model to characterize the in vivo efficacy of LVsh5/C46 (Cal-1) vector to engineer cellular resistance to HIV-1 pathogenesis. Human CD34+ hematopoietic stem/progenitor cells (HSPC) either nonmodified or transduced with LVsh5/C46 vector were transplanted to generate control and treatment groups, respectively. Control and experimental groups displayed similar engraftment and multilineage hematopoietic differentiation that included robust CD4+ T-cell development. Splenocytes isolated from the treatment group were resistant to both R5- and X4-tropic HIV-1 during ex vivo challenge experiments. Treatment group animals challenged with R5-tropic HIV-1 displayed significant protection of CD4+ T-cells and reduced viral load within peripheral blood and lymphoid tissues up to 14 weeks postinfection. Gene-marking and transgene expression were confirmed stable at 26 weeks post-transplantation. These data strongly support the use of LVsh5/C46 lentiviral vector in gene and cell therapeutic applications for inhibition of HIV-1 infection.

Item Description

2162-2531
10.1038/mtna.2015.10