Alternative splicing and genetic variation of mhc-e: implications for rhesus cytomegalovirus-based vaccines

• Published in: Communications biology Vol. 5; no. 1; pp. 1387 - 13
• Main Authors: Brochu, Hayden, Wang, Ruihan, Tollison, Tammy, Pyo, Chul-Woo, Thomas, Alexander, Tseng, Elizabeth, Law, Lynn, Picker, Louis J., Gale, Michael, Geraghty, Daniel E., Peng, Xinxia
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 19.12.2022; Nature Publishing Group; Nature Portfolio
• Subjects: 38/23; 38/77; 38/91; 45/22; 45/90; 631/114/2785; 631/208/212; 631/250/248; 631/250/590/1867; Alleles; Alternative Splicing; Animals; Biology; Biomedical and Life Sciences; CD8 antigen; Cytomegalovirus; Cytomegalovirus Vaccines; E protein; Genetic diversity; Genetic Variation; Genomics; Histocompatibility antigen HLA; Histocompatibility Antigens Class I - genetics; HLA-E Antigens; Humans; Isoforms; Life Sciences; Lymphocytes T; Macaca mulatta; Major histocompatibility complex; Simian Immunodeficiency Virus; Translation; Vaccines
• ISSN: 2399-3642; 2399-3642
• DOI: 10.1038/s42003-022-04344-2

Rhesus cytomegalovirus (RhCMV)-based vaccination against Simian Immunodeficiency virus (SIV) elicits MHC-E-restricted CD8+ T cells that stringently control SIV infection in ~55% of vaccinated rhesus macaques (RM). However, it is unclear how accurately the RM model reflects HLA-E immunobiology in humans. Using long-read sequencing, we identified 16 Mamu-E isoforms and all Mamu-E splicing junctions were detected among HLA-E isoforms in humans. We also obtained the complete Mamu-E genomic sequences covering the full coding regions of 59 RM from a RhCMV/SIV vaccine study. The Mamu-E gene was duplicated in 32 (54%) of 59 RM. Among four groups of Mamu-E alleles: three ~5% divergent full-length allele groups (G1, G2, G2_LTR) and a fourth monomorphic group (G3) with a deletion encompassing the canonical Mamu-E exon 6, the presence of G2_LTR alleles was significantly (p = 0.02) associated with the lack of RhCMV/SIV vaccine protection. These genomic resources will facilitate additional MHC-E targeted translational research. The alternative splicing and genetic variations across the whole MHC-E locus of Rhesus Macaques (Mamu-E) are analysed, which provides a foundation for more comprehensive research of Mamu-E and informs translational research of CMV-based vaccines.