The race between viral immune evasion and the MHC class I antigen processing pathway

Area of Science:

• Immunology
• Virology
• Molecular Biology

Background:

• Viral immune evasion is critical for pathogen persistence and disease severity.
• Major Histocompatibility Complex class I (MHC-I) antigen processing and presentation (APP) is a key target for viral immune evasion.
• Viruses disrupt MHC-I pathways to evade CD8+ cytotoxic T lymphocyte (CTL) surveillance while balancing natural killer (NK) cell responses.

Purpose of the Study:

• To review and synthesize the diverse mechanisms viruses use to interfere with the MHC-I APP pathway.
• To integrate innate immune antagonism and endoplasmic reticulum stress into a framework for understanding viral control of MHC-I.
• To explore the translational implications of viral manipulation of antigen presentation.

Main Methods:

• Literature review and synthesis of mechanistic insights across DNA and RNA virus families.
• Integration of data on viral strategies affecting antigen substrate availability, proteasomal peptide generation, TAP-dependent peptide import, and peptide loading.
• Analysis of viral modulation of MHC-I trafficking, surface degradation, allele-selective presentation, and nonclassical MHC circuits like HLA-E.

Main Results:

• Viruses employ coordinated, multi-node interference to functionally rewire the MHC-I APP pathway.
• Viral strategies include limiting antigen substrates, altering peptide generation, disrupting TAP function, and interfering with peptide loading.
• Viruses modulate MHC-I presentation to evade CTLs without triggering excessive NK cell activation, fine-tuning immune visibility.

Conclusions:

• Understanding viral manipulation of the MHC-I APP pathway provides a unified framework for viral immune evasion.
• Viral strategies are diverse and target multiple steps in antigen processing and presentation.
• This mechanistic synthesis has significant translational implications for developing antiviral therapies and improving immune surveillance.