The impact of HLA polymorphism on herpesvirus infection and disease

Abstract

Human Leukocyte Antigens (HLA) are cell surface molecules, central in coordinating innate and adaptive immune responses, that are targets of strong diversifying natural selection by pathogens. Of these pathogens, human herpesviruses have a uniquely ancient relationship with our species, where coevolution likely has reciprocating impact on HLA and viral genomic diversity. Consistent with this notion, genetic variation at multiple HLA loci is strongly associated with modulating immunity to herpesvirus infection. Here, we synthesize published genetic associations of HLA with herpesvirus infection and disease, both from case/control and genome-wide association studies. We analyze genetic associations across the eight human herpesviruses and identify HLA alleles that are associated with diverse herpesvirus-related phenotypes. We find that whereas most HLA genetic associations are virus- or disease-specific, HLA-A*01 and HLA-A*02 allotypes may be more generally associated with immune susceptibility and control, respectively, across multiple herpesviruses. Connecting genetic association data with functional corroboration, we discuss mechanisms by which diverse HLA and cognate receptor allotypes direct variable immune responses during herpesvirus infection and pathogenesis. Together, this review examines the complexity of HLA-herpesvirus interactions driven by differential T cell and Natural Killer cell immune responses.

Proteogenomics analysis of human tissues using pangenomes

“…We further investigated the 294 highly modified genes that contained a large number of variants using the String network 43 . Multiple highly connected networks are revealed across Laminin genes, including LAMC3, LAMA5, LAMA3, and LAMA; and HLA genes including HLA-A, HLA-B and HLA-C and HLA-DRB1; this aligns with expectations since HLA loci are known for their high polymorphism 51, 52 . ( Figure 5A ) Interestingly, after performing enrichment analysis using the 294 genes; Twenty genes (TG, LAMA5, SYNE2, HLA-DRB1, AHNAK2, MKI67, FLG, HLA-C, PRUNE2, HLA-A, MUC16, HLA-B, HLA-DPB1, FRAS1, MUC12, OBSCN, TTN, FCGBP, NEB, PLIN4]) were previously reported by Vahdati and Wagner 53 as genes whose haplotype networks have significantly more squares in their networks than expected by chance alone (Table 1 – original manuscript 53 ).…”

“…We further investigated the 294 highly modified genes that contained a large number of variants using the String network 43 . Multiple highly connected networks are revealed across Laminin genes, including LAMC3, LAMA5, LAMA3, and LAMA; and HLA genes including HLA-A, HLA-B and HLA-C and HLA-DRB1; this aligns with expectations since HLA loci are known for their high polymorphism 51,52 . (Figure 5A)…”

Immunogenetics special issue 2023: Immunogenetics of infectious disease

“…Characterised by reciprocal genomic mutations, the long-term coevolution between herpesviruses and their host provides some of the best-characterised examples of host adaptation and immune evasion strategies. Palmer and Norman discuss the co-evolution of humans with herpesviruses and the impact of HLA and NK cell receptor variation on infection and its course (Palmer and Norman 2023 ). Genetic associations across the eight human herpesviruses are analysed, and HLA alleles that are associated with diverse herpesvirus-related phenotypes are identified.…”