Primary Sequence-Intrinsic Immune Evasion by Viral Proteins Guides CTL-Based Vaccine Strategies

Viruses use a range of sophisticated strategies to evade detection by cytotoxic T-lymphocytes (CTLs) within host cells. Beyond elaborating dedicated viral proteins that disrupt the MHC class I antigen-presentation machinery, some viruses possess intrinsic, cis-acting genome-encoded elements that interfere with antigen processing and display. These protein features, including G-quadruplex motifs, repetitive peptide sequences, and rare-codon usage, counterintuitively limit production of proteins critical to virus survival, particularly during latency. By slowing viral protein synthesis, these features reduce antigen production and proteosomal degradation, ultimately limiting the generation of peptides for MHC I presentation. These built-in evasion tactics enable viruses to remain "invisible" to CTLs during latency. While these primary sequence intrinsic immune evasion (PSI) mechanisms are well-described in select herpesviruses, emerging evidence suggests that they may also play a critical role in RNA viruses. How these proteins are made, rather than what they functionally target, determines their immune evasion properties. Understanding PSI mechanisms could rationally inform the design of engineered viral antigens with altered or removed evasion elements to restore antigen CTL priming and activation. Such vaccine strategies have the potential to enhance immune recognition, improve clearance of chronically infected cells, and contribute to the treatment of persistent viral infections and virus-associated cancers.