1. Antiviral effects of autologous CD4 T cells genetically modified with a conditionally replicating lentiviral vector expressing long antisense to HIV.
- Author
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Tebas P, Stein D, Binder-Scholl G, Mukherjee R, Brady T, Rebello T, Humeau L, Kalos M, Papasavvas E, Montaner LJ, Schullery D, Shaheen F, Brennan AL, Zheng Z, Cotte J, Slepushkin V, Veloso E, Mackley A, Hwang WT, Aberra F, Zhan J, Boyer J, Collman RG, Bushman FD, Levine BL, and June CH
- Subjects
- Adoptive Transfer methods, Adult, Antiviral Agents adverse effects, Antiviral Agents metabolism, Antiviral Agents pharmacology, CD4-Positive T-Lymphocytes metabolism, CD4-Positive T-Lymphocytes physiology, Female, Genetic Therapy adverse effects, Genetic Vectors adverse effects, Genetic Vectors metabolism, Genetic Vectors pharmacology, HIV Infections genetics, HIV Infections immunology, HIV-1 immunology, Humans, Lentivirus metabolism, Lentivirus physiology, Male, Middle Aged, Oligonucleotides administration & dosage, Oligonucleotides genetics, Oligonucleotides, Antisense administration & dosage, Oligonucleotides, Antisense adverse effects, Oligonucleotides, Antisense genetics, Transduction, Genetic methods, Viral Load drug effects, Virus Replication genetics, CD4-Positive T-Lymphocytes transplantation, Genetic Therapy methods, HIV Infections therapy, HIV-1 genetics, Lentivirus genetics, Oligonucleotides, Antisense pharmacology
- Abstract
We report the safety and tolerability of 87 infusions of lentiviral vector–modified autologous CD4 T cells (VRX496-T; trade name, Lexgenleucel-T) in 17 HIV patients with well-controlled viremia. Antiviral effects were studied during analytic treatment interruption in a subset of 13 patients. VRX496-T was associated with a decrease in viral load set points in 6 of 8 subjects (P = .08). In addition, A → G transitions were enriched in HIV sequences after infusion, which is consistent with a model in which transduced CD4 T cells exert antisense-mediated genetic pressure on HIV during infection. Engraftment of vector-modified CD4 T cells was measured in gut-associated lymphoid tissue and was correlated with engraftment in blood. The engraftment half-life in the blood was approximately 5 weeks, with stable persistence in some patients for up to 5 years. Conditional replication of VRX496 was detected periodically through 1 year after infusion. No evidence of clonal selection of lentiviral vector–transduced T cells or integration enrichment near oncogenes was detected. This is the first demonstration that gene-modified cells can exert genetic pressure on HIV. We conclude that gene-modified T cells have the potential to decrease the fitness of HIV-1 and conditionally replicative lentiviral vectors have a promising safety profile in T cells.
- Published
- 2013
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