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Non-classical class I human leukocyte antigens (HLA) molecules are known to modulate the function of cytotoxic cells (NK and T CD8+) during viral infection by interacting with inhibitory/activating receptors. However, little is known about the HLA-E/-F genetic variability on arbovirus infections. We evaluated by massive parallel sequencing the full HLA-E/-F genetic diversity among patients infected during the arbovirus (ZIKV, DENV, and CHIKV) outbreak leading to a broad range of neurological complications in the Brazilian State of Pernambuco. In parallel, healthy blood donors from the same area were also studied. Plink and R software were used for genetic association study. To limit the false-positive results and enhance the reliability of the results, we adopted P- values <0.01 as significant levels. Compared to controls, the HLA-F alleles: −1610 C (rs17875375), +1383 G (rs17178385), and +3537 A (rs17875384), all in complete linkage disequilibrium with each other (r2 = 1), were overrepresented in patients presenting peripheral spectrum disorders (PSD). The HLA-F *Distal-D haplotype that harbored the −1610 C allele exhibited a trend increase in PSD group. No associations were found for HLA-E. Our findings showed that the HLA-F genetic background seems to be more important than HLA-E on the susceptibility to PSD complications. • Little is known about the HLA-E/-F gene variability in arbovirus infections. • HLA-F is associated with arbovirus-induced peripheral spectrum disorders. • A HLA-F promoter/3′UTR variant conferred susceptibility to arbovirus infections. • HLA-E gene variability was not associated with arbovirus complications. • HLA-F rather than HLA-E confers susceptibility to arbovirus complications. [ABSTRACT FROM AUTHOR]

The HLA-G molecule presents immunomodulatory properties that might inhibit immune responses when interacting with specific Natural Killer and T cell receptors, such as KIR2DL4, ILT2 and ILT4. Thus, HLA-G might influence the outcome of situations in which fine immune system modulation is required, such as autoimmune diseases, transplants, cancer and pregnancy. The majority of the studies regarding the HLA-G gene variability so far was restricted to a specific gene segment (i.e., promoter, coding or 3′ untranslated region), and was performed by using Sanger sequencing and probabilistic models to infer haplotypes. Here we propose a massively parallel sequencing (NGS) with a bioinformatics strategy to evaluate the entire HLA-G regulatory and coding segments, with haplotypes inferred relying more on the straightforward haplotyping capabilities of NGS, and less on probabilistic models. Then, HLA-G variability was surveyed in two admixed population samples of distinct geographical regions and demographic backgrounds, Cyprus and Brazil. Most haplotypes (promoters, coding, 3′UTR and extended ones) were detected both in Brazil and Cyprus and were identical to the ones already described by probabilistic models, indicating that these haplotypes are quite old and may be present worldwide. [ABSTRACT FROM AUTHOR]

HLA-E is a non-classical Human Leucocyte Antigen class I gene with immunomodulatory properties. Whereas HLA-E expression usually occurs at low levels, it is widely distributed amongst human tissues, has the ability to bind self and non-self antigens and to interact with NK cells and T lymphocytes, being important for immunosurveillance and also for fighting against infections. HLA-E is usually the most conserved locus among all class I genes. However, most of the previous studies evaluating HLA-E variability sequenced only a few exons or genotyped known polymorphisms. Here we report a strategy to evaluate HLA-E variability by next-generation sequencing (NGS) that might be used to other HLA loci and present the HLA-E haplotype diversity considering the segment encoding the entire HLA-E mRNA (including 5′UTR, introns and the 3′UTR) in two African population samples, Susu from Guinea–Conakry and Lobi from Burkina Faso. Our results indicate that (a) the HLA-E gene is indeed conserved, encoding mainly two different protein molecules; (b) Africans do present several unknown HLA-E alleles presenting synonymous mutations; (c) the HLA-E 3′UTR is quite polymorphic and (d) haplotypes in the HLA-E 3′UTR are in close association with HLA-E coding alleles. NGS has proved to be an important tool on data generation for future studies evaluating variability in non-classical MHC genes. [ABSTRACT FROM AUTHOR]