This review describes the development of pathway-centered mechanistic synthesis across DNA and RNA virus families and 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.
Abstract
Abstract 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.
Peptides presented by class-I Human Leukocyte Antigen (HLA-I) proteins provide the basis of immune surveillance. Conversely, reduced surface HLA-I expression is a hallmark of immune evasion in cancers, which confounds the identification of peptide antigens and neoantigens. Here, we outline a system (HLA-Shuttle) for in vitro manipulation of cells with engineered components of the HLA-I processing pathway that improves recovery of the immunopeptidome of immunologically “cold” tumors.
HLA-Shuttle is comprised of an engineered variant of the HLA class I chaperone tapasin that bypasses its native degradation and ER retention signals, enabling improved expression and escape from the ER. HLA-Shuttle provides a continuum of chaperoning activity for HLA-I complexes from their point of assembly in the ER to the cell surface, improving antigen presentation in those cells.
Our data suggest that HLA-Shuttle functions in a multimodal fashion, both enhancing HLA-I complex production in the ER while stabilizing the folded conformation of HLA-I molecules globally. This is evidenced by increased surface expression of HLA-I, while cellular trafficking assays and single particle tracking reveal an extension of their cell-surface lifetimes and microdomain formation, implying an enhancement in their stability. Leveraging this technology, we captured the immunopeptidomes of neuroblastoma cell lines. We observed improved immunoprecipitation of HLA-I complexes, which correlated with a significant expansion of the observable immunopeptidome in immunologically cold neuroblastoma cells. Following bioinformatics analysis to search for therapeutically relevant peptides, we identified multiple novel tumor associated antigens (TAAs) from both known and novel cancer immunotherapy targets.
In conclusion, HLA-Shuttle restores antigen presentation in immunologically cold tumor cells, facilitating identification of TAAs with favorable therapeutic potential.
T32 Fellowship
Classical and Non-Classical Antigen Presenting Cells (APC)
Daniel Hwang, Molly C. Erdman, Santosh Adhikari et al.· Journal of Immunology· 0 citations
Classical swine fever remains a major threat to global pig production systems, despite decades of sustained control endeavours. Its causative agent classical swine fever virus (CSFV) employs a highly coordinated set of immune evasion mechanisms to weaken host antiviral defences and permit extensive viral replication. A central focus of this strategy is the antigen-presentation machinery, where CSFV disrupts both major histocompatibility complex class (MHC)-I and MHC-II pathways in macrophages and dendritic cells, which are its primary immune cell reservoirs. By suppressing interferon signaling, dysregulating NF-kB activation, and impairing the maturation of antigen-presenting cells, CSFV compromises peptide processing, co-stimulatory signaling, and T-cell priming. These defects propagate through the adaptive immune system, leading to delayed cytotoxic responses, inadequate CD4
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T-cell help, and impaired humoral immunity. CSFV simultaneously reshapes macrophage polarization, drives profound dendritic cell dysfunction, induces lymphoid apoptosis, and modulates γδ T-cell activity in a manner that correlates with viral virulence. In addition, viral remodeling of intracellular organelles further limits antigen presentation and exacerbates immunopathology. Together, these interconnected mechanisms create a permissive cellular environment that facilitates viral persistence and amplifies disease severity. Understanding how CSFV manipulates antigen-presentation pathways provides crucial insights for the design of next-generation vaccines and therapeutic strategies capable of restoring robust antiviral immunity.
Nagarajan Siddharthan, Muruganantham Vijay, M. Roopa et al.· Asian Pacific Journal of Tro...· 0 citations
Influenza A virus can evade detection by the adaptive immune system, as evidenced by low vaccine efficacy and reinfections during human challenge studies. Like all successful viruses, influenza A virus regulates host antiviral responses, and it encodes multiple immunomodulatory proteins for this purpose. One such viral protein, PA-X, is an endoribonuclease that suppresses host gene expression during infection. Here we investigate the impact of PA-X on MHC I antigen presentation, a key process for host detection of intracellular pathogens.
To investigate PA-X dependent changes during infection, we infected primary human donor air liquid interface (ALI) cultures of airway epithelial cells with wild type (WT) or PA-X deficient H3N2 influenza A virus. Using single cell RNA sequencing, we detected changes in gene expression of antigen processing and presentation. We then investigated surface and intracellular MHC I protein levels using flow cytometry and MHC I trafficking to the cell surface using an acid strip time course.
The influenza A viral protein PA-X significantly reduced expression of antigen processing and presentation genes in infected epithelial cells. Both surface and intracellular MHC I levels were significantly reduced in WT influenza-infected ALI cultures compared to mock-infected cultures or cultures infected with PA-X deficient virus. Furthermore, PA-X activity halved the rate of MHC I trafficking to the surface during infection.
Through regulation of MHC I gene expression, PA-X decreases the rate of MHC I trafficking during infection. This likely delays detection by antigen-specific T cells, allowing the virus to replicate and spread, particularly in hosts with prior immunity to influenza A virus, and contributing to the continued success of this virus. Future work will investigate the functional impacts of PA-X disruption of MHC I using immunopeptidomics and in vivo studies.
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Viral Immunology (VIR)
Alessandra C. Setaro, M. Gaglia· Journal of Immunology· 0 citations
The main mechanisms of antigen acquisition, endocytic/lysosomal factors controlling MHCII-restricted processing and presentation, and evidence linking lysosomal dysfunction to autoimmunity are explored.
Gabriele Sergio Colangelo, Kyra J Cowan, Federico Riccardi Sirtori et al.· Journal of Immunology· 0 citations
We propose that persistent, human-adapted DNA organisms shape postnatal immunity by focusing responses on functionally constrained epitopes within tissue niches. Here, we examine rapidly evolving RNA viruses and tumors through that lens. We propose that their persistence is promoted by 2 coupled mechanisms: (i) immunodominance steering toward mutable “decoy” epitopes that contribute little to durable control, and (ii) antigen display control that reduces cytotoxic T lymphocyte (CTL) recognition while preserving inhibitory natural killer (NK) receptor engagement, for example via HIV Nef/Vpu effects on HLA-A and HLA-B and through HLA-E/NKG2A pathways. Tumors show analogous vulnerabilities through altered class I expression and reinforcement of inhibitory signaling. Using HIV as the primary model, we distinguish HLA-associated viral adaptation mechanisms and highlight evidence consistent with a subset of adaptations that preserve detectable T-cell recognition while being associated with reduced antiviral effector function. We then consider the degree to which this framework can be extended to hepatitis C virus (HCV), influenza, SARS-CoV-2, and tumor immunoediting. We conclude with 3 vaccine design principles: prioritize epitopes where substitutions carry measurable fitness costs, avoid immunogens dominated by mutable targets, and account for antigen presentation context and inhibitory NK signaling when evaluating epitope choice. We distinguish established observations from testable predictions and outline experiments needed to evaluate the framework. We frame the analysis conditionally on the keystone-imprinting premise, which is developed in companion work.
Simon Mallal, A. Asiaee· Pathogens and Immunity· 3 citations
Nonclassical major histocompatibility complex class I (MHC-I) molecules, including human leukocyte antigen E (HLA-E), HLA-F, HLA-G, MHC-I-related protein 1 (MR1), and the CD1 family, constitute a conserved antigen-presenting system that regulates immune surveillance, tissue homeostasis, and tolerance through specialized interactions with innate and unconventional T cells. Although these molecules have long been implicated in cancer, infection, autoimmunity, and transplantation, their distinct immunobiology and therapeutic potential have largely been considered in isolation. Recent advances in structural immunology, single-cell and spatial profiling, engineered immune cell technologies, and early clinical studies have established nonclassical MHC-I pathways as tractable targets for immunotherapy. In this review, we synthesize the biology, disease-associated functions, and therapeutic targeting of these molecules, integrating immune checkpoint blockade, antibody-based therapeutics, and MR1- and CD1-restricted cellular immunotherapies into a unified framework. We further highlight shared immunological principles, emerging clinical translation, and opportunities for universal, off-the-shelf immune interventions.
