The role of mRNA-galsomes and LNPs in enhancing HIV-specific T cell responses across various lymphoid organs.

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.