Conditional Immune Escape during Chronic Simian Immunodeficiency Virus Infection

Area of Science:

• Immunology
• Virology
• Genetics

Background:

• Therapeutic anti-HIV CD8 T cells require targeting epitopes resistant to mutations.
• Immune escape in T cell epitopes is influenced by host genetics and epitope variation tolerance.
• Previous work indicated conditional immune escape during acute simian immunodeficiency virus (SIV) infection.

Purpose of the Study:

• To test if conditional immune escape extends to chronic SIV infection.
• To determine if preserved epitopes can elicit CD8 T cell responses.
• To investigate the role of Major Histocompatibility Complex (MHC) heterozygosity in preserving epitope immunogenicity.

Main Methods:

• Deep sequencing of SIV in Mauritian cynomolgus macaques (MCMs) with M3 MHC homozygous and heterozygous haplotypes.
• Analysis of epitope variation in relation to MHC genotype.
• Assessment of chronic CD8 T cell responses against specific epitopes.

Main Results:

• Epitopes were categorized into three groups (A, B, C) based on variation.
• Category B epitopes accumulated variants in M3-homozygous MCMs but less so in M3-heterozygous MCMs.
• Chronic CD8 T cell responses were better preserved in M3-heterozygous MCMs.

Conclusions:

• Epitopes escaping in MHC-homozygous hosts are preserved and immunogenic in MHC-heterozygous hosts.
• Heterozygosity delays immune escape, allowing epitopes to retain immunogenicity during chronic infection.
• The findings support the conditional immune escape hypothesis, highlighting the potential for broader epitope presentation to delay viral escape.