Abstract

Despite advances in antiretroviral therapy (ART), individuals with advanced HIV disease continue to face significant 
challenges related to immune dysfunction and persistent viral reservoirs. Therapeutic messenger RNA (mRNA) 
vaccines have emerged as a promising intervention aimed at restoring immune competence and achieving sustained 
viral control beyond the capabilities of ART. These vaccines are engineered to encode HIV-specific antigens and 
immunomodulatory molecules, stimulating robust cytotoxic T lymphocyte responses while reversing T-cell 
exhaustion. Unlike prophylactic vaccines, therapeutic mRNA constructs are designed to engage dysfunctional 
immunity, reprogram host immune responses, and potentially target latent viral reservoirs. Key innovations, such as 
self-amplifying RNA, codon optimization, and lipid nanoparticle (LNP) delivery systems, enhance the stability, 
potency, and specificity of the immune response. Preclinical studies and early-phase clinical trials demonstrate 
promising results in reducing viral rebound and improving immune activation in advanced disease settings. In this 
review, a narrative methodology was employed to synthesize findings from experimental models, vaccine trials, and 
immunopathological studies. Despite existing challenges, including viral diversity, immune senescence, and delivery 
constraints, therapeutic mRNA vaccines hold significant potential as components of functional cure strategies. Their 
integration into comprehensive HIV treatment paradigms may offer a transformative path toward durable viral 
suppression, particularly in populations where ART alone fails to fully restore immune function.