Despite major efforts, no therapeutic HIV-1 vaccine tested to date has been successful in eliciting effective anti-viral responses while at the same time avoiding the emergence of viral escape variants. We recently demonstrated that lipid-based delivery of a mRNA vaccine encoding the HIV-1 Gag antigen to dendritic cells from HIV-1 positive patients expanded autologous HIV-1 specific T cell responses in vitro and primed the induction of HIV-1 specific CD8 T cell immunity in vivo in mice. However, we also found that the induction of T cells responses by the mRNA vaccine was counteracted by the early secretion of type I IFN by host cells and a subsequent type I IFN-mediated suppression of vaccine mRNA translation into protein antigen. In addition, the vaccine used for these proof-of-principle experiments was based on a defined antigen that cannot induce a sufficiently broad T cell coverage to control viral escape. In this project we aim to further increase the strength of mRNA vaccine-induced CD8 T cell responses by circumventing the type I IFN-induced negative effects on vaccine mRNA translation and by the inclusion of mRNA encoding co-stimulatory molecules. Furthermore, we will enhance the breadth of the elicited HIV-1 specific immune responses by improving the antigenic coverage of the elicited memory T cells. Taken together, these approaches will result in a superior mRNA vaccine that could ultimately develop into a universal immunotherapy against HIV-1.