Maturation of Dendritic Cells for Enhanced Activation of Anti-HIV-1 CD8(+) T Cell Immunity

Maturation of dendritic cells (DC) to enhance their capacity to activate T cell immunity to HIV-1 is a key step in immunotherapy of HIV-1 infection with DC. We compared maturation of DC derived from HIV-1-uninfected subjects and infected subjects on antiretroviral therapy (ART) or ART naïve by CD40 ligand (CD40L) and combinations of TLR3 ligand polyinosinic:polycytidylic acid [poly(I:C)] and inflammatory cytokines IFN-gamma, IFN-alpha, IL-1beta, and TNF-alpha. The greatest levels of virus-specific IFN-gamma production by CD8(+) T cells were stimulated by DC treated with CD40L, followed by DC treated with the poly(I:C)-cytokine combination. The highest levels of IL-12p70 were produced by DC treated with CD40L + IFN-gamma, followed by CD40L and the poly(I:C)-cytokine combination. Neutralization of IL-12p70 indicated that it was only partially involved in direct enhancement of antiviral CD8(+) T cell activity. DC stimulation of antiviral CD8(+) T cell reactivity was enhanced by activated CD4(+) T cells at low concentrations but was suppressed at higher CD4(+) T cell concentrations. Maturation of DC with CD40L obviated the need for CD4(+) T cell help and overcame this suppressive activity. Finally, we showed that DC from HIV-1-infected subjects on ART, which were treated with the poly(I:C)-cytokine combination, retained the capacity to produce IL-12p70 and activate anti-HIV-1 CD8(+) T cell responses after restimulation with CD40L, with or without IFN-gamma. Thus, DC from HIV-1-infected subjects can be engineered with CD40L or a poly(I:C)-cytokine combination for enhancing CD8(+) T cell responses to HIV-1, which has potential applications in HIV-1 immunotherapy.