Therapeutic mRNA Vaccines for HIV: Immune Restoration and Viral Control in Advanced Disease

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. Keywords: Therapeutic mRNA vaccines, Advanced HIV disease, Immune restoration, Viral reservoir control, Cytotoxic T lymphocyte responses.