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Infectious and inflammatory diseases have repeatedly shown strong genetic associations within the major histocompatibility complex (MHC); however, the basis for these associations remains elusive. To define host genetic effects on the outcome of a chronic viral infection, we performed genome-wide association analysis in a multiethnic cohort of HIV-1 controllers and progressors, and we analyzed the effects of individual amino acids within the classical human leukocyte antigen (HLA) proteins. We identified > 300 genome-wide significant single-nucleotide polymorphisms (SNPs) within the MHC and none elsewhere. Specific amino acids in the HLA-B peptide binding groove, as well as an independent HLA-C effect, explain the SNP associations and reconcile both protective and risk HLA alíeles. These results implicate the nature of the HLA-viral peptide interaction as the major factor modulating durable control of HIV infection.

Whole genome comparisons identified introgression from archaic to modern humans. Our analysis of highly polymorphic human leukocyte antigen (HLA) class I, vital immune system components subject to strong balancing selection, shows how modern humans acquired the HLA-B*73 allele in west Asia through admixture with archaic humans called Denisovans, a likely sister group to the Neandertals. Virtual genotyping of Denisovan and Neandertal genomes identified archaic HLA haplotypes carrying functionally distinctive alleles that have introgressed into modern Eurasian and Oceanian populations. These alleles, of which several encode unique or strong ligands for natural killer cell receptors, now represent more than half the HLA alleles of modern Eurasians and also appear to have been later introduced into Africans. Thus, adaptive introgression of archaic alleles has significantly shaped modern human immune systems.

Interferon (IFN)-α is the earliest cytokine signature observed in individuals at risk for type 1 diabetes (T1D), but the effect of IFN-α on the antigen repertoire of HLA Class I (HLA-I) in pancreatic β-cells is unknown. Here we characterize the HLA-I antigen presentation in resting and IFN-α-exposed β-cells and find that IFN-α increases HLA-I expression and expands peptide repertoire to those derived from alternative mRNA splicing, protein cis- splicing and post-translational modifications. While the resting β-cell immunopeptidome is dominated by HLA-A-restricted peptides, IFN-α largely favors HLA-B and only marginally upregulates HLA-A, translating into increased HLA-B-restricted peptide presentation and activation of HLA-B-restricted CD8 + T cells. Lastly, islets of patients with T1D show preferential HLA-B hyper-expression when compared with non-diabetic donors, and islet-infiltrating CD8 + T cells reactive to HLA-B-restricted granule peptides are found in T1D donors. Thus, the inflammatory milieu of insulitis may skew the autoimmune response toward alternative epitopes presented by HLA-B, hence recruiting T cells with a distinct repertoire that may be relevant to T1D pathogenesis. Interferon-α (IFN-α) is linked to type 1 diabetes (T1D), but how IFN-α impacts auto-antigen presentation is still unclear. Here the authors compare resting and IFN-α-treated islet β cells in vitro to find IFN-α inducing increased HLA-B expression, presentation of alternative epitopes, and activation of HLA-B-restricted T cells, thereby serving clues for T1D onset.

Allopurinol, a commonly prescribed medication for gout and hyperuricemia, is a frequent cause of severe cutaneous adverse reactions (SCAR), which include the drug hypersensitivity syndrome, Stevens-Johnson syndrome, and toxic epidermal necrolysis. The adverse events are unpredictable and carry significant morbidity and mortality. To identify genetic markers for allopurinol-SCAR, we carried out a case-control association study. We enrolled 51 patients with allopurinol-SCAR and 228 control individuals (135 allopurinol-tolerant subjects and 93 healthy subjects from the general population), and genotyped for 823 SNPs in genes related to drug metabolism and immune response. The initial screen revealed strong association between allopurinol-SCAR and SNPs in the MHC region, including BAT3 (encoding HLA-B associated transcript 3), MSH5 (mutS homolog 5), and MICB (MHC class I polypeptide-related sequence B) ($P<10^{-7}$). We then determined the alleles of HLA loci A, B, C, and DRB1. The HLA-B*5801 allele was present in all (100%) 51 patients with allopurinol-SCAR, but only in 20 (15%) of 135 tolerant patients [odds ratio 580.3 (95% confidence interval, 34.4-9780.9); corrected P value=4.7× 10-24] and in 19 (20%) of 93 of healthy subjects [393.51 (23.23-6665.26); corrected P value=8.1× 10-18]. HLA alleles A*3303, Cw*0302, and DRB1*0301 were in linkage disequilibrium and formed an extended haplotype with HLA-B*5801. Our results indicated that allopurinol-SCAR is strongly associated with a genetic predisposition in Han Chinese. In particular, HLA-B*5801 allele is an important genetic risk factor for this life-threatening condition.

HIV a moving target In order to determine whether HIV is adapting to the human leukocyte antigen (HLA) alleles, such as HLA-B * 57, B * 57 and B * 51, that mediate successful control of the virus, viral sequences and HLA types were analysed in more than 500 HIV-infected subjects drawn from North America, the Caribbean, Europe, Africa, Australasia and Asia. The results reveal that HIV is evolving at the population level in response to immune selection pressure. Whilst this does not indicate that HIV is necessarily 'winning' the evolutionary struggle against humans, it does suggest that successful HIV vaccines — like those against influenza — will need to keep pace with a changing immunological landscape. This paper traces the adaptation of HIV to HLA alleles in 2,500 HIV-infected subjects and demonstrates a strong correlation between the prevalence of escape mutations within well characterized epitopes and the prevalence of the respective HLA alleles, thereby providing evidence that the virus is indeed adapting to effective immune responses. The rapid and extensive spread of the human immunodeficiency virus (HIV) epidemic provides a rare opportunity to witness host–pathogen co-evolution involving humans. A focal point is the interaction between genes encoding human leukocyte antigen (HLA) and those encoding HIV proteins. HLA molecules present fragments (epitopes) of HIV proteins on the surface of infected cells to enable immune recognition and killing by CD8 + T cells; particular HLA molecules, such as HLA-B*57, HLA-B*27 and HLA-B*51, are more likely to mediate successful control of HIV infection 1 . Mutation within these epitopes can allow viral escape from CD8 + T-cell recognition. Here we analysed viral sequences and HLA alleles from >2,800 subjects, drawn from 9 distinct study cohorts spanning 5 continents. Initial analysis of the HLA-B*51-restricted epitope, TAFTIPSI (reverse transcriptase residues 128–135), showed a strong correlation between the frequency of the escape mutation I135X and HLA-B*51 prevalence in the 9 study cohorts ( P = 0.0001). Extending these analyses to incorporate other well-defined CD8 + T-cell epitopes, including those restricted by HLA-B*57 and HLA-B*27, showed that the frequency of these epitope variants ( n = 14) was consistently correlated with the prevalence of the restricting HLA allele in the different cohorts (together, P  < 0.0001), demonstrating strong evidence of HIV adaptation to HLA at a population level. This process of viral adaptation may dismantle the well-established HLA associations with control of HIV infection that are linked to the availability of key epitopes, and highlights the challenge for a vaccine to keep pace with the changing immunological landscape presented by HIV.

Hypersensitivity reactions to abacavir are tightly associated with HLA-B*5701. In this global, multicenter, prospective, randomized study, 1956 patients with HIV-1 infection who had not previously received abacavir were randomly assigned to undergo HLA-B*5701 screening or to receive the standard of care. Screening eliminated immunologically confirmed hypersensitivity reaction to abacavir in this predominantly white population. In this case, a pharmacogenetic test can prevent the toxic effects of this drug. Hypersensitivity reactions to abacavir are tightly associated with HLA-B*5701. In this study of patients with HIV-1 infection, HLA-B*5701 screening eliminated immunologically confirmed hypersensitivity reaction to abacavir. Pharmacogenetic testing is not widely used in routine clinical practice to optimize drug choice or clinical management. 1 This gap between scientific knowledge and clinical application may be explained by the fact that the successful incorporation of a pharmacogenetic test into routine practice requires a combination of high-level evidence that can be generalized to diverse clinical settings, widespread availability of cost-effective and reliable laboratory tests, and effective strategies to incorporate testing into routine clinical practice. Abacavir is a nucleoside reverse-transcriptase inhibitor with activity against the human immunodeficiency virus (HIV), available for once-daily use in combination with other antiretroviral agents, that has . . .

Human leukocyte antigen (HLA) genes are the most polymorphic in the human genome. They play a pivotal role in the immune response and have been implicated in numerous human pathologies, especially autoimmunity and infectious diseases. Despite their importance, however, they are rarely characterized comprehensively because of the prohibitive cost of standard technologies and the technical challenges of accurately discriminating between these highly related genes and their many allelles. Here we demonstrate a high-resolution, and cost-effective methodology to type HLA genes by sequencing, which combines the advantage of long-range amplification, the power of high-throughput sequencing platforms, and a unique genotyping algorithm. We calibrated our method for HLA-A, -B, -C, and -DRB1 genes with both reference cell lines and clinical samples and identified several previously undescribed alleles with mismatches, insertions, and deletions. We have further demonstrated the utility of this method in a clinical setting by typing five clinical samples in an Illumina MiSeq instrument with a 5-d turnaround. Overall, this technology has the capacity to deliver low-cost, high-throughput, and accurate HLA typing by multiplexing thousands of samples in a single sequencing run, which will enable comprehensive disease-association studies with large cohorts. Furthermore, this approach can also be extended to include other polymorphic genes.

Allotypes of the natural killer (NK) cell receptor KIR3DL1 vary in both NK cell expression patterns and inhibitory capacity upon binding to their ligands, HLA-B Bw4 molecules, present on target cells. Using a sample size of over 1,500 human immunodeficiency virus (HIV) + individuals, we show that various distinct allelic combinations of the KIR3DL1 and HLA-B loci significantly and strongly influence both AIDS progression and plasma HIV RNA abundance in a consistent manner. These genetic data correlate very well with previously defined functional differences that distinguish KIR3DL1 allotypes. The various epistatic effects observed here for common, distinct KIR3DL1 and HLA-B Bw4 combinations are unprecedented with regard to any pair of genetic loci in human disease, and indicate that NK cells may have a critical role in the natural history of HIV infection.

Ankylosing spondylitis is a common inflammatory rheumatic disease that affects the axial skeleton, causing characteristic inflammatory back pain, which can lead to structural and functional impairments and a decrease in quality of life. New imaging techniques and therapies have substantially changed the management of this disease in the past decade. Whether inhibition of radiographic progression and structural damage can be reached with available drugs is as yet unclear. Furthermore, treatment with non-steroidal anti-inflammatory agents and physiotherapy remains an important approach to long-term management of patients with ankylosing spondylitis. The new treatment options with tumour necrosis factor blockers seems a breakthrough for patients refractory to conventional treatment.

Epidemiological studies have associated certain human disease outcomes with particular killer cell Ig-like receptor (KIR) and HLA genotypes. However, the functional explanation for these associations is poorly understood, because the KIRs were initially described as natural killer (NK) cell inhibitory receptors with specificity for HLA molecules on their cellular targets. Yet resolution of infections is often associated with genotypic pairing of inhibitory KIRs with their cognate HLA ligands. Recent studies in mice indicate a second role for MHC-specific inhibitory receptors, i.e., self-MHC recognition confers functional competence on the NK cell to be triggered through their activation receptors, a process termed licensing. As a result, licensed NK cells with self-MHC-specific receptors are more readily activated as compared with unlicensed NK cells without self-MHC-specific receptors. Such results predict that human NK cells may undergo a similar process. Here, we examined the human NK cell subset expressing KIR3DL1, the only known KIR specific for HLA-Bw4 alleles. The KIR3DL1⁺ subset in normal donors with two HLA-B-Bw4 genes displayed increased responsiveness to tumor stimulation compared with the KIR3DL1⁺ subset from individuals with only one or no Bw4 genes. By contrast, NK cells lacking KIR3DL1 showed no differences. Therefore, these data indicate that particular KIR and HLA alleles are associated with more responsive NK cells, strongly suggesting that human NK cells are also subjected to NK cell licensing, and providing a potential functional explanation for the influence of KIR and HLA genes in disease as well as interindividual differences in NK cell potency.