Conceptual Design of a Dual-Function saRNA-LNP Vaccine Encoding Mosaic HIV Antigens and Intracellular Antiviral Peptides: Framework for Therapeutic HIV Vaccination

Introduction. Although antiretroviral therapy (ART) effectively suppresses Human Immunodeficiency Virus (HIV), it does not eliminate viral reservoirs, and lifelong ART remains necessary. We outline a conceptual framework for a therapeutic vaccine that combines two complementary strategies: (1) induction of broad antiviral immunity using conserved mosaic antigens, and (2) intracellular interference with viral replication through engineered antiviral peptides. This saRNA-LNP platform aims to achieve durable viral control without lifelong ART by simultaneously targeting immune evasion and viral replication pathways.

Methods. The proposed platform integrates (1) mosaic immunogens, such as self-amplifying RNA (saRNA) encoding computationally selected epitopes from Gag, Pol, Env, Tat and Rev, based on NetMHCpan predictions and the Los Alamos National Laboratory HIV database, aiming for broad clade coverage (>95%); and (2) antiviral peptides, including mRNA encoding inhibitors such as LEDGIN-like peptides that block integrase-LEDGF/p75 binding and dominant-negative reverse transcriptase variants (YIDD mutants). These are formulated in lipid nanoparticles (LNPs) containing DOTAP and anti-CD40 ligands to enhance dendritic cell targeting. Epitope conservation was assessed with IEDB, while Rosetta docking was used to model peptide binding to viral enzymes.

Results. In silico analyses suggest high population coverage (~98% for HLA-I/II), sustained antigen expression for over 14 days, and strong predicted peptide–enzyme interactions (Rosetta energies <–7.5 kcal/mole). BLASTp comparisons indicated low cross-reactivity with human proteins. Note that these findings are entirely in silico.

Conclusion. This conceptual design proposes a dual-function vaccine that seeks to enhance HIV-specific immune responses while simultaneously disrupting viral replication as a novel antirretroviral therapy for HIV. The approach is quite ambitious and remains at an early theoretical stage. Experimental validation will be essential to determine its feasibility as a future therapeutic vaccination strategy.