mRNA Vaccine Platforms Targeting HIV 1 Envelope Glycoproteins: Current Progress and Future Directions

Abstract

Human immunodeficiency virus type 1 remains a major global health challenge, with persistent transmission despite advances in antiretroviral therapy and preventive interventions. The viral envelope glycoproteins gp120 and gp41, organized as trimeric spikes on the virion surface, mediated host cell entry and represented the principal targets of neutralizing antibodies; however, extensive glycan shielding, conformational masking, and genetic variability historically hindered vaccine development. The purpose of this review was to critically evaluate current progress in mRNA vaccine platforms encoding HIV 1 envelope glycoproteins and to examine their potential to overcome longstanding immunological barriers. A structured narrative synthesis of recent preclinical and early clinical studies, integrated with advances in structural biology and molecular engineering, was undertaken to assess emerging evidence. Accumulating data indicated that mRNA platforms permitted precise encoding of stabilized envelope trimers, germline targeting constructs, and mosaic immunogens, resulting in improved antigen expression and enhanced induction of neutralizing antibody precursors in animal models and early human trials. Nevertheless, induction of broadly neutralizing antibodies with sufficient breadth and durability remained elusive. mRNA-based approaches provided unprecedented flexibility and translational promise for HIV vaccine design, yet required iterative immunogen optimization and rigorous clinical evaluation to achieve meaningful protective efficacy. Keywords: HIV 1, mRNA vaccine, Envelope glycoprotein, Broadly neutralizing antibodies, Structural vaccinology.