"The Dendritic Cell Vaccination in AIDS"GCOE Program Seminar(Global Education Seminar)
Control of HIV-1 replication, sometimes leading to undetectable viremia in the absence of highly active antiretroviral therapy (HAART), has been associated with magnitude and breadth of T-cell response preferentially targeting Gag, T-cell polyfunctionality and proliferation and direct in vitro CD8+ T-cell HIV-suppressive capacity. In an effort to raise these antiviral T-cell responses, we performed therapeutic dendritic cell (DC) vaccination in 6 HIV-1 subtype B-infected patients, stable under HAART. DC were derived from autologous monocytes, transfected with HIV-1 strain IIIB-derived mRNA encoding Gag and a chimeric Tat-Rev-Nef protein and administered intradermally and subcutaneously, while patients remained on HAART.
DC vaccine preparation and administration were successful in all patients and only mild adverse events were seen. Following DC vaccination, there was a significant concomitant increase in magnitude and breadth of HIV-1-specific interferon (IFN)-γ T-cell response to Gag but not to Tat, Rev or Nef, and in T-cell proliferative capacity. Breadth of IFN-γ response and T-cell proliferation were both correlated with CD4+ and CD8+ polyfunctional T-cells expressing at least 2 out of 4 functional markers tested (IFN-γ, IL-2, TNF , CD107a). Strikingly, DC vaccination significantly increased the capacity of autologous CD8+ T-cells to inhibit in vitro superinfection of patient autologous CD4+ T-cells with the vaccine-related IIIB virus; there was also inhibition of superinfection with some but not all other HIV-1 strains tested. This HIV-1-inhibitory activity, indicative of improved antiviral response, was correlated with magnitude and breadth of Gag-specific IFN-γ response. In conclusion, the stimulation of antiviral cellular immune responses, which have been associated with control of HIV-1, underscores the potential of DC vaccination in the treatment of HIV-1.
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○Arinobu Tojo, M.D.,Ph.D. (Division of Molecular Therapy),
Toshiki Watanabe, M.D.,Ph.D. (MGS, Laboratory of Tumor Cell Biology)