title: Antiviral effects of autologous CD4 T cells genetically modified with a conditionally replicating lentiviral vector expressing long antisense to HIV.
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.
authors.affiliation: Department of Medicine and Center for AIDS Research, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Pablo
authors.initials: P
authors.lastname: Tebas
authors.forename: David
authors.initials: D
authors.lastname: Stein
authors.forename: Gwendolyn
authors.initials: G
authors.lastname: Binder-Scholl
authors.forename: Rithun
authors.initials: R
authors.lastname: Mukherjee
authors.forename: Troy
authors.initials: T
authors.lastname: Brady
authors.forename: Tessio
authors.initials: T
authors.lastname: Rebello
authors.forename: Laurent
authors.initials: L
authors.lastname: Humeau
authors.forename: Michael
authors.initials: M
authors.lastname: Kalos
authors.forename: Emmanouil
authors.initials: E
authors.lastname: Papasavvas
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Montaner
authors.forename: Daniel
authors.initials: D
authors.lastname: Schullery
authors.forename: Farida
authors.initials: F
authors.lastname: Shaheen
authors.forename: Andrea L
authors.initials: AL
authors.lastname: Brennan
authors.forename: Zhaohui
authors.initials: Z
authors.lastname: Zheng
authors.forename: Julio
authors.initials: J
authors.lastname: Cotte
authors.forename: Vladimir
authors.initials: V
authors.lastname: Slepushkin
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Veloso
authors.forename: Adonna
authors.initials: A
authors.lastname: Mackley
authors.forename: Wei-Ting
authors.initials: WT
authors.lastname: Hwang
authors.forename: Faten
authors.initials: F
authors.lastname: Aberra
authors.forename: Jenny
authors.initials: J
authors.lastname: Zhan
authors.forename: Jean
authors.initials: J
authors.lastname: Boyer
authors.forename: Ronald G
authors.initials: RG
authors.lastname: Collman
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.forename: Bruce L
authors.initials: BL
authors.lastname: Levine
authors.forename: Carl H
authors.initials: CH
authors.lastname: June
mesh_terms: D019264:Adoptive Transfer / Q000379:methods; D000328:Adult; D000998:Antiviral Agents / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000502:physiology / Q000637:transplantation*; D005260:Female; D015316:Genetic Therapy / Q000009:adverse effects / Q000379:methods*; D005822:Genetic Vectors / Q000009:adverse effects / Q000378:metabolism / Q000494:pharmacology; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D006801:Humans; D016086:Lentivirus / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008297:Male; D008875:Middle Aged; D009841:Oligonucleotides / Q000008:administration & dosage / Q000235:genetics; D016376:Oligonucleotides, Antisense / Q000008:administration & dosage / Q000009:adverse effects / Q000235:genetics / Q000494:pharmacology*; D014161:Transduction, Genetic / Q000379:methods; D019562:Viral Load / Q000187:drug effects; D014779:Virus Replication / Q000235:genetics
chemical_list: D000998:Antiviral Agents; D009841:Oligonucleotides; D016376:Oligonucleotides, Antisense; C580773:lexgenleucel-T