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: Pablo Tebas, David Stein, Gwendolyn Binder-Scholl, Rithun Mukherjee, Troy Brady, Tessio Rebello, Laurent Humeau, Michael Kalos, Emmanouil Papasavvas, Luis J Montaner, Daniel Schullery, Farida Shaheen, Andrea L Brennan, Zhaohui Zheng, Julio Cotte, Vladimir Slepushkin, Elizabeth Veloso, Adonna Mackley, Wei-Ting Hwang, Faten Aberra, Jenny Zhan, Jean Boyer, Ronald G Collman, Frederic D Bushman, Bruce L Levine, Carl H June
• Journal: Blood (Blood) Vol. 121 Issue 9 Pg. 1524-33 (Feb 28 2013) ISSN: 1528-0020 [Electronic] United States
• PMID: 23264589 (Publication Type: Clinical Trial, Journal Article, Multicenter Study, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiviral Agents
• Oligonucleotides
• Oligonucleotides, Antisense
• lexgenleucel-T

Topics

• Adoptive Transfer (methods)
• Adult
• Antiviral Agents (adverse effects, metabolism, pharmacology)
• CD4-Positive T-Lymphocytes (metabolism, physiology, transplantation)
• Female
• Genetic Therapy (adverse effects, methods)
• Genetic Vectors (adverse effects, metabolism, pharmacology)
• HIV Infections (genetics, immunology, therapy)
• HIV-1 (genetics, immunology)
• Humans
• Lentivirus (genetics, metabolism, physiology)
• Male
• Middle Aged
• Oligonucleotides (administration & dosage, genetics)
• Oligonucleotides, Antisense (administration & dosage, adverse effects, genetics, pharmacology)
• Transduction, Genetic (methods)
• Viral Load (drug effects)
• Virus Replication (genetics)