title: Engineering Cellular Resistance to HIV-1 Infection In Vivo Using a Dual Therapeutic Lentiviral Vector.
abstract: 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.
authors: Calimmune, Inc., Los Angeles, California, USA.
authors: Bryan P
authors: BP
authors: Burke
authors: Division of Hematology-Oncology and the UCLA Center for AIDS Research (CFAR), David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors: Bernard R
authors: BR
authors: Levin
authors: Calimmune, Inc., Los Angeles, California, USA.
authors: Jane
authors: J
authors: Zhang
authors: School of Nursing at UCLA, UCLA AIDS Institute, Los Angeles, California, USA.
authors: Anna
authors: A
authors: Sahakyan
authors: School of Nursing at UCLA, UCLA AIDS Institute, Los Angeles, California, USA.
authors: Joshua
authors: J
authors: Boyer
authors: Calimmune, Inc., Los Angeles, California, USA.
authors: Maria V
authors: MV
authors: Carroll
authors: Calimmune, Inc., Los Angeles, California, USA.
authors: Joanna Camba
authors: JC
authors: Colón
authors: Calimmune, Inc., Los Angeles, California, USA.
authors: Naomi
authors: N
authors: Keech
authors: Division of Hematology-Oncology and the UCLA Center for AIDS Research (CFAR), David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors: Valerie
authors: V
authors: Rezek
authors: Division of Hematology-Oncology and the UCLA Center for AIDS Research (CFAR), David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors: Gregory
authors: G
authors: Bristol
authors: School of Nursing at UCLA, UCLA AIDS Institute, Los Angeles, California, USA.
authors: Erica
authors: E
authors: Eggers
authors: School of Nursing at UCLA, UCLA AIDS Institute, Los Angeles, California, USA.
authors: Ruth
authors: R
authors: Cortado
authors: Calimmune, Inc., Los Angeles, California, USA.
authors: Maureen P
authors: MP
authors: Boyd
authors: Calimmune, Inc., Los Angeles, California, USA.
authors: Helen
authors: H
authors: Impey
authors: School of Nursing at UCLA, UCLA AIDS Institute, Los Angeles, California, USA.
authors: Saki
authors: S
authors: Shimizu
authors: School of Nursing at UCLA, UCLA AIDS Institute, Los Angeles, California, USA.
authors: Emily L
authors: EL
authors: Lowe
authors: Calimmune, Inc., Los Angeles, California, USA.
authors: Gene-Errol E
authors: GE
authors: Ringpis
authors: Division of Hematology-Oncology and the UCLA Center for AIDS Research (CFAR), David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors: Sohn G
authors: SG
authors: Kim
authors: Division of Hematology-Oncology and the UCLA Center for AIDS Research (CFAR), David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors: Dimitrios N
authors: DN
authors: Vatakis
authors: Calimmune, Inc., Los Angeles, California, USA.
authors: Louis R
authors: LR
authors: Breton
authors: Calimmune, Inc., Los Angeles, California, USA.
authors: Jeffrey S
authors: JS
authors: Bartlett
authors: Department of Microbiology, Immunology, and Molecular Genetics, David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors: Irvin S Y
authors: IS
authors: Chen
authors: Division of Hematology-Oncology and the UCLA Center for AIDS Research (CFAR), David Geffen School of Medicine at UCLA, Los Angeles, California, USA.
authors: Scott G
authors: SG
authors: Kitchen
authors: School of Nursing at UCLA, UCLA AIDS Institute, Los Angeles, California, USA.
authors: Dong Sung
authors: DS
authors: An
authors: Calimmune, Inc., Los Angeles, California, USA.
authors: Geoff P
authors: GP
authors: Symonds