Enhancing potency of anti-HIV chimeric immune receptor (CIR) (128.5)

Abstract

Abstract Immunotherapies that have the potential to eradicate reservoirs of HIV infected cells may be useful to suppress or cure HIV/AIDS. in combination with current antiviral drug therapies. T cells expressing chimeric immune receptors (CIR) through gene modification ("designer T cells") can be redirected to kill HIV-infected cells. Previously, an anti-HIV CIR, CD4-ζ (1st generation), was created to bind to HIV-1 gp120 antigen through its CD4 extracellular domain and induction of signaling through cytoplasmic CD3ζ chain. However, the adoptive transfer of autologous CD4-ζ T cells to HIV/AIDS patients failed to control the viral infection in clinical trials. To improve potency, our laboratory has created 2nd generation anti-HIV designer T cells that incorporate CD28 costimulation (CD4-CD28-ζ). 2nd generation designer T cells kill HIV-Env expressing Jurkat cells and HIV-1 infected CEM-SS cells as well or better than 1st generation designer T cells. Stimulation with anti-CD4 mAb induces more IL2 production in 2nd generation than 1st generation designer T cells. In addition, 2nd generation designer T cells showed significantly better proliferative response upon culture with HIV-Env expressing HeLa cells or HIV-1 infected CEM-SS cells. These data suggest that gene modified CD8+ T cells could be an effective therapy to eradicate HIV+ cells during and after anti-retroviral therapy. We hypothesize that CD28 domain in the CIR will confer a benefit of longer T cell survival after infusion into HIV patients. Research supported by NIH, R21.