1区 · 医学
Article
作者: Tebas, Pablo ; Stein, David ; Binder-Scholl, Gwendolyn ; Mukherjee, Rithun ; Brady, Troy ; Rebello, Tessio ; Humeau, Laurent ; Kalos, Michael ; Papasavvas, Emmanouil ; Montaner, Luis J. ; Schullery, Daniel ; Shaheen, Farida ; Brennan, Andrea L. ; Zheng, Zhaohui ; Cotte, Julio ; Slepushkin, Vladimir ; Veloso, Elizabeth ; Mackley, Adonna ; Hwang, Wei-Ting ; Aberra, Faten ; Zhan, Jenny ; Boyer, Jean ; Collman, Ronald G. ; Bushman, Frederic D. ; Levine, Bruce L. ; June, Carl H.
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.