[Show abstract][Hide abstract] ABSTRACT: DNA vaccination is a novel immunization strategy that has great potential for the development of vaccines and immune therapeutics. This strategy has been highly effective in mice, but is less immunogenic in non-human primates and in humans. Enhancing DNA vaccine potency remains a challenge. It is likely that antigen-presenting cells (APCs), and especially dendritic cells (DCs), play a significant role in the presentation of the vaccine antigen to the immune system. A new study reports the synergistic recruitment, expansion and activation of DCs in vivo by high-mobility group box 1 (HMGB1) protein. Such combinational strategies for delivering vaccine in a single, simple platform will hypothetically bolster the cellular immunity in vivo. Here, we combined plasmid encoding human immunodeficiency virus-1 (HIV-1) Gag and Env with an HMGB1 plasmid as a DNA adjuvant in BALB/c mice (by intramuscular immunization via electroporation), and humoral and cellular responses were measured. Co-administration of this potent immunostimulatory adjuvant strongly enhanced the cellular interferon-gamma (IFN-gamma) and humoral immune response compared with that obtained in mice immunized with vaccine only. Our results show that co-immunization with HMGB1 can have a strong adjuvant activity, driving strong cellular and humoral immunity that may be an effective immunological adjuvant in DNA vaccination against HIV-1.
[Show abstract][Hide abstract] ABSTRACT: Chronic viral infection is characterized by the functional impairment of virus-specific T-cell responses. Recent evidence
has suggested that the inhibitory receptor programmed death 1 (PD-1) is specifically upregulated on antigen-specific T cells
during various chronic viral infections. Indeed, it has been reported that human immunodeficiency virus (HIV)-specific T cells
express elevated levels of PD-1 and that this expression correlates with the viral load and inversely with CD4+ T-cell counts. More importantly, antibody blockade of the PD-1/PD-L1 pathway was sufficient to both increase and stimulate
virus-specific T-cell proliferation and cytokine production. However, the mechanisms that mediate HIV-induced PD-1 upregulation
are not known. Here, we provide evidence that the HIV type 1 (HIV-1) accessory protein Nef can transcriptionally induce the
expression of PD-1 during infection in vitro. Nef-induced PD-1 upregulation requires its proline-rich motif and the activation
of the downstream kinase p38. Further, inhibition of Nef activity by p38 MAPK inhibitor effectively blocked PD-1 upregulation,
suggesting that p38 MAPK activation is an important initiating event in Nef-mediated PD-1 expression in HIV-1-infected cells.
These data demonstrate an important signaling event of Nef in HIV-1 pathogenesis.
Full-text · Article · Oct 2008 · Journal of Virology