ID: 258: Therapeutic immunostimulation mediated by RIG-I pathway activation

Abstract

The development of novel therapeutics to treat human pathogenic RNA viral infections such as influenza, as well as emerging pathogens such as dengue and chikungunya, is an important strategic goal, aimed at reducing the spread of infection and improving human health. In recent studies, we developed an optimized AU-rich RNA motif (M8) that specifically triggered a robust antiviral immune response via the cytosolic pattern recognition receptor RIG-I, and generated a protective antiviral immune response in vivo and in vitro that blocked influenza and chikungunya infection (Goulet et al., 2013; Chiang et al., 2015). The adjuvant properties of M8 were also examined in combination with virus-like particles (VLP) expressing the influenza H5N1 hemagglutinin and neuraminidase as immunogens. In combination with VLP, M8 increased the neutralizing antibody response to VLP immunization and protected mice against lethal influenza challenge. M8-VLP immunization also led to long-term protective responses against influenza infection in mice, compared to animals immunized with VLP alone. Uniquely, immunization with M8-VLP stimulated a TH1-biased CD4 T cell response, as determined by increased TH1 cytokine levels in CD4 T cells and increased IgG2 levels in sera. Collectively, these data demonstrate that a sequence-optimized, RIG-I specific agonist is an effective antiviral agent and a potent adjuvant that can be utilized to increase the immunogenicity of influenza VLP vaccination and dramatically improve humoral and cellular mediated protective responses against human pathogenic viruses.