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Prolonged Control of Viremia After Transfer of Autologous CD4 T Cells Genetically Modified with a Lentiviral Vector Expressing Long Antisense to HIV env (VRX496)
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Reported by Jules Levin
CROI 2010
Pablo Tebas*1, D. Stein2, L. Zifchak1, A. Seda2, G. Binder3, F. Aberra4, R. Collman1, G. McGarrity5, B. Levine3, and C. June3
1Center for AIDS Research, University of Pennsylvania, Philadelphia, PA,2Jacobi Medical Center, Bronx, NY, 3 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia PA,4Hospital of the University of Pennsylvania, Philadelphia, PA; and 5VIRxSYS Corporation, Gaithersburg, MD
Abstract
Background: The recent description of the control of HIV viral replication in a patient with acute myeloid leukemia who received a homozygous for CCR5-Δ32 allogeneic stem cell transplant has revitalized the interest in immune-based strategies to control HIV infection in the absence of antiretroviral therapy. The ability of autologous transfer of CD4 T cells genetically modified with HIV env antisense to control HIV is unknown.
Methods: In an ongoing phase I/II trial, 17 HIV-1-infected subjects who were fully suppressed on ART received over a period up to 14 weeks 3 or 6 infusions each of 1010 autologous CD4 T cells transduced with a lentiviral vector encoding a 937 nucleotide HIV env antisense construct (VRX496) and expanded ex vivo. To evaluate the effects this therapy had on viral set points and CD4 counts, eligible subjects underwent scheduled treatment interrup-tion (STI) six weeks after the last infusion.
Results: All subjects received infusions, and 76% (13/17) underwent STI; 62% (8/13) of subjects who underwent STI were evaluable for the efficacy endpoint. 88% (7/8) of evaluable subjects had a decrease in viral load setpoint (range -0.26 to -.98), and one subject’s viral load has not. Here we report this subject, a 52 year old African American woman with well controlled viral replication on a regimen of TFV/FTC/Atazanavir/ritonavir, who re-ceived 3 infusions of 1010 autologous CD4 T cells transduced with VRX496. Six weeks after the last infusion antiretroviral therapy was discontinued. Her total billirubin decreased from 3 mg/ml to 0.6 mg/dL. During the follow up period of + 104 days she has maintained an HIV RNA viral load below the limit of detection and a CD4 cell count greater than 1200 cells/µL. The patient has been infected with HIV-1 for at least 6 years, her HIV RNA viral load before the initiation of ART was 366,667 copies per ml and her nadir CD4 cell count 302 cells/mm3. At entry her CD4 cells count was 772 cells/µL (49%), increasing to 2200 cells/µL (62%) after receiving 3 infusions of modified T cells. Initially up to 13% of the circulating PBMC carried the lentiviral insert, and no evidence of clonal expansion, with persistence declining to 0.2% at day +76 after STI.
Conclusions: This is the first report of prolonged control of HIV viremia in the absence of antiretroviral therapy after the infusion of genetically modified autologous T cells. We are evaluating ge-netic, viral and immunologic factors to explain this dramatic result.
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