Abstract
mRNA nanoparticles have been investigated in the context of prophylactic vaccination against HIV, but their effectivity has not been widely investigated in therapeutic vaccination. It has been suggested that a profound CD8+ T cell response within lymphoid tissues, a primary site for viral reservoirs, is crucial for achieving optimal viral control, potentially correlating with protection. This study aimed to evaluate the effectiveness of mRNA lipid nanoparticles (LNPs), including a modified variant containing α-galactosylceramide as an adjuvant, termed galsomes. C57BL/6 mice were immunized intramuscularly with nucleoside-modified mRNA encoding ovalbumin (li80tOVA), revealing that mRNA-galsomes induced slightly higher proliferation levels of li80tOVA-specific CD8+ T cells in lymphoid tissues across various anatomical sites compared with mRNA-LNPs. In addition, immunization with nucleoside-modified HIV-1 Gag mRNA elicited a notable Gag-specific immune response in both formulations even at low mRNA doses. Remarkably, mRNA-galsomes induced lower polyfunctional responses in CD4+ T cells, but similar polyfunctional responses in CD8+ T cells in the spleen compared with mRNA-LNPs. Importantly, the Gag-specific CD8+ T cells demonstrated cytolytic capacity against target cells in both the spleen and lymphoid tissues, including gut-associated lymph nodes. These findings underscore the potential of both mRNA-galsomes and mRNA-LNPs as tools for therapeutic vaccination against HIV.