Human herpesvirus diversity is altered in HLA class I binding peptides.

Herpesviruses are ubiquitous, genetically diverse DNA viruses, with long-term presence in humans associated with infrequent but significant pathology. Human leukocyte antigen (HLA) class I presents intracellularly derived peptide fragments from infected tissue cells to CD8+ T and natural killer cells, thereby directing antiviral immunity. Allotypes of highly polymorphic HLA class I are distinguished by their peptide binding repertoires. Because this HLA class I variation is a major determinant of herpesvirus disease, we examined if sequence diversity of virus proteins reflects evasion of HLA presentation. Using population genomic data from Epstein­Barr virus (EBV), human cytomegalovirus (HCMV), and Varicella­Zoster virus, we tested whether diversity differed between the regions of herpesvirus proteins that can be recognized, or not, by HLA class I. Herpesviruses exhibit lytic and latent infection stages, with the latter better enabling immune evasion. Whereas HLA binding peptides of lytic proteins are conserved, we found that EBV and HCMV proteins expressed during latency have increased peptide sequence diversity. Similarly, latent, but not lytic, herpesvirus proteins have greater population structure in HLA binding than nonbinding peptides. Finally, we found patterns consistent with EBV adaption to the local HLA environment, with less efficient recognition of EBV isolates by high-frequency HLA class I allotypes. Here, the frequency of CD8+ T cell epitopes inversely correlated with the frequency of HLA class I recognition. Previous analyses have shown that pathogen-mediated natural selection maintains exceptional polymorphism in HLA residues that determine peptide recognition. Here, we show that HLA class I peptide recognition impacts diversity of globally widespread pathogens.

Adaptive Admixture of HLA Class I Allotypes Enhanced Genetically Determined Strength of Natural Killer Cells in East Asians.

Human natural killer (NK) cells are essential for controlling infection, cancer, and fetal development. NK cell functions are modulated by interactions between polymorphic inhibitory killer cell immunoglobulin-like receptors (KIR) and polymorphic HLA-A, -B, and -C ligands expressed on tissue cells. All HLA-C alleles encode a KIR ligand and contribute to reproduction and immunity. In contrast, only some HLA-A and -B alleles encode KIR ligands and they focus on immunity. By high-resolution analysis of KIR and HLA-A, -B, and -C genes, we show that the Chinese Southern Han (CHS) are significantly enriched for interactions between inhibitory KIR and HLA-A and -B. This enrichment has had substantial input through population admixture with neighboring populations, who contributed HLA class I haplotypes expressing the KIR ligands B*46:01 and B*58:01, which subsequently rose to high frequency by natural selection. Consequently, over 80% of Southern Han HLA haplotypes encode more than one KIR ligand. Complementing the high number of KIR ligands, the CHS KIR locus combines a high frequency of genes expressing potent inhibitory KIR, with a low frequency of those expressing activating KIR. The Southern Han centromeric KIR region encodes strong, conserved, inhibitory HLA-C-specific receptors, and the telomeric region provides a high number and diversity of inhibitory HLA-A and -B-specific receptors. In all these characteristics, the CHS represent other East Asians, whose NK cell repertoires are thus enhanced in quantity, diversity, and effector strength, likely augmenting resistance to endemic viral infections.

Systematic analysis reveals tumor-enhancing and -suppressing microRNAs in Drosophila epithelial tumors.

Despite their emergence as an important class of noncoding RNAs involved in cancer cell transformation, invasion, and migration, the precise role of microRNAs (miRNAs) in tumorigenesis remains elusive. To gain insights into how miRNAs contribute to primary tumor formation, we conducted an RNA sequencing (RNA-Seq) analysis of Drosophila wing disc epithelial tumors induced by knockdown of a neoplastic tumor-suppressor gene (nTSG) lethal giant larvae (lgl), combined with overexpression of an active form of oncogene Ras (RasV12 ), and identified 51 mature miRNAs that changed significantly in tumorous discs. Followed by in vivo tumor enhancer and suppressor screens in sensitized genetic backgrounds, we identified 10 tumor-enhancing (TE) miRNAs and 11 tumor-suppressing (TS) miRNAs that contributed to the nTSG defect-induced tumorigenesis. Among these, four TE and three TS miRNAs have human homologs. From this study, we also identified 29 miRNAs that individually had no obvious role in enhancing or alleviating tumorigenesis despite their changed expression levels in nTSG tumors. This systematic analysis, which includes both RNA-Seq and in vivo functional studies, helps to categorize miRNAs into different groups based on their expression profile and functional relevance in epithelial tumorigenesis, whereas the evolutionarily conserved TE and TS miRNAs provide potential therapeutic targets for epithelial tumor treatment.