The Race between Viral Immune Evasion and the MHC Class I Antigen Processing Pathway

Viral immune evasion of the major histocompatibility complex class I (MHC-I) antigen processing and presentation (APP) pathway is a centerpiece of the art of deception that enables persistence, reinfection, and severe disease. It does so by blunting peptide-MHC-I (pMHC-I) display, weakening CD8+ cytotoxic T lymphocyte (CTL) surveillance, and balancing the counterpressure imposed by natural killer (NK) cell missing-self responses. Rather than relying on a single trick, viruses deploy coordinated, multinode interference that functionally rewires the APP assembly line. These deceptive strategies include limiting antigen substrate availability, reshaping proteasomal peptide generation, sabotaging transporters associated with antigen processing (TAP)-dependent peptide import, disrupting peptide-loading complex-assisted editing, misdirecting MHC-I trafficking, and accelerating surface pMHC-I degradation. In parallel, many viruses fine-tune immune visibility through allele-selective modulation and nonclassical MHC circuits such as human leukocyte antigen E (HLA-E), thereby optimizing CTL evasion without inducing overwhelming NK activation. This review, therefore, describes the development of pathway-centered mechanistic synthesis across DNA and RNA virus families. We further integrate innate immune antagonism, endoplasmic reticulum stress, antigen-presentation competence, cross-presentation limits, and virus-shaped peptide landscapes into a unified framework for understanding viral control of MHC-I output and its translational implications.