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89 GENE THERAPY: POTENT CYTOTOXIC T LYMPHOCYTE ACTIVITY BY ADENO-ASSOCIATED VIRUS/CORE-HEPATITIS C VIRUS GENE DELIVERY INTO DENDRITIC CELLS.
  1. M. Chiriva-Internati1,2,
  2. F. Grizzi4,
  3. E. Frezza2,
  4. E. Cobos3
  1. 1Department of Microbiology and Immunology
  2. 2Department of Surgery
  3. 3Internal Medicine, Texas Tech University Health Sciences Center and Southwest Cancer Treatment and Research Center, Lubbock, TX
  4. 4Scientific Direction, Istituto Clinico Humanitas, Rozzano, Milan, Italy

Abstract

Purpose Many cases of chronic hepatitis C virus (HCV) infection are resistant to conventional therapies. Such cases might be treated by cell-mediated immunotherapy as cytotoxic T lymphocytes (CTL) are the main mechanism by which viral infections are cleared. The HCV core gene, being well conserved among HCV types, may be an appropriate antigen for targeting HCV-infected cells.

Methods Here a series of five recombinant adeno-associated virus (rAAV) vectors carrying the full length (aa1-190) or autoimmune domain-depleted (AIDD) versions of core were used to load dendritic cells (DC), which, in turn, stimulated anti-core CTL. The AAV vectors were found to be able to transduce 88 to 95% of DC and the transduced DC displayed higher levels of CD80, CD83, CD86, and CD1a over controls. One vector, AAV/core(49-180)/Neo, with both autoimmune domains deleted from core, stimulated comparable core-positive target killing to the other versions yet stimulated significantly lower levels of "self " killing of core negative-targets, either of autologous PBMC targets (p = .002) or HLA-matched HepG2 liver cancer cells (p = .001).

Results The resulting CTL populations displayed higher IFN-g expression, higher CD8:CD4 ratios, and lower CD56:CD8 ratios than controls. The rAAV loading-derived CD8+ T cells had more CD69+ cells and the CD4+ T populations had fewer CD25+ cells than controls.

Summary and Conclusion AAV/core(49-180)/Neo, containing a dual AIDD core gene, may be particularly useful for clinical treatments as it stimulates lower "self " recognition but stimulates robust anticore CTL activity.

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