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Heterozygosity of Human leukocyte antigen (HLA) class I genes is linked to beneficial outcomes after HIV infection, presumably through greater breadth of HIV epitope presentation and cytotoxic T cell response. Distinct allotype pairs, however, differ in the extent to which they bind shared sets of peptides. We developed a functional divergence metric that measures pairwise complementarity of allotype-associated peptide binding profiles. Greater functional divergence for pairs of HLA-A and/or HLA-B allotypes was associated with slower AIDS progression and independently with enhanced viral load control. The metric predicts immune breadth at the peptide level rather than gene level and redefines HLA heterozygosity as a continuum differentially affecting disease outcome. Functional divergence may affect response to additional infections, vaccination, immunotherapy, and other diseases where HLA heterozygote advantage occurs.

Studies have demonstrated that at least 20% of individuals infected with SARS-CoV-2 remain asymptomatic1-4. Although most global efforts have focused on severe illness in COVID-19, examining asymptomatic infection provides a unique opportunity to consider early immunological features that promote rapid viral clearance. Here, postulating that variation in the human leukocyte antigen (HLA) loci may underly processes mediating asymptomatic infection, we enrolled 29,947 individuals, for whom high-resolution HLA genotyping data were available, in a smartphone-based study designed to track COVID-19 symptoms and outcomes. Our discovery cohort (n = 1,428) comprised unvaccinated individuals who reported a positive test result for SARS-CoV-2. We tested for association of five HLA loci with disease course and identified a strong association between HLA-B*15:01 and asymptomatic infection, observed in two independent cohorts. Suggesting that this genetic association is due to pre-existing T cell immunity, we show that T cells from pre-pandemic samples from individuals carrying HLA-B*15:01 were reactive to the immunodominant SARS-CoV-2 S-derived peptide NQKLIANQF. The majority of the reactive T cells displayed a memory phenotype, were highly polyfunctional and were cross-reactive to a peptide derived from seasonal coronaviruses. The crystal structure of HLA-B*15:01-peptide complexes demonstrates that the peptides NQKLIANQF and NQKLIANAF (from OC43-CoV and HKU1-CoV) share a similar ability to be stabilized and presented by HLA-B*15:01. Finally, we show that the structural similarity of the peptides underpins T cell cross-reactivity of high-affinity public T cell receptors, providing the molecular basis for HLA-B*15:01-mediated pre-existing immunity.

CD8+ T cell responses restricted by MHC-E, a nonclassical MHC molecule, have been associated with protection in an SIV/rhesus macaque model. The biological relevance of HLA-E-restricted CD8+ T cell responses in HIV infection, however, remains unknown. In this study, CD8+ T cells responding to HIV-1 Gag peptides presented by HLA-E were analyzed. Using in vitro assays, we observed HLA-E-restricted T cell responses to what we believe to be a newly identified subdominant Gag-KL9 as well as a well-described immunodominant Gag-KF11 epitope in T cell lines derived from chronically HIV-infected patients and also primed from healthy donors. Blocking of the HLA-E/KF11 binding by the B7 signal peptide resulted in decreased CD8+ T cell responses. KF11 presented via HLA-E in HIV-infected cells was recognized by antigen-specific CD8+ T cells. Importantly, bulk CD8+ T cells obtained from HIV-infected individuals recognized infected cells via HLA-E presentation. Ex vivo analyses at the epitope level showed a higher responder frequency of HLA-E-restricted responses to KF11 compared with KL9. Taken together, our findings of HLA-E-restricted HIV-specific immune responses offer intriguing and possibly paradigm-shifting insights into factors that contribute to the immunodominance of CD8+ T cell responses in HIV infection.

Genetic susceptibility to myasthenia gravis (MG) associates with specific HLA alleles and haplotypes at the class I and II regions in various populations. Previous studies have only examined alleles at a limited number of HLA loci that defined only broad serotypes or alleles defined at the protein sequence level. Consequently, genetic variants in noncoding and untranslated HLA gene segments have not been fully explored but could also be important determinants for MG. To gain further insight into the role of HLA in MG, we applied next-generation sequencing to analyze sequence variation at eleven HLA genes in early-onset (EO) and late-onset (LO) non-thymomatous MG patients positive for the acetylcholine receptor (AChR) antibodies and ethnically matched controls from Italy, Norway, and Sweden. For all three populations, alleles and haplotype blocks present on the ancestral haplotype AH8.1 were associated with risk in AChR-EOMG patients. HLA-B*08:01:01:01 was the dominant risk allele in Italians (OR = 3.28, P = 1.83E-05), Norwegians (OR = 3.52, P = 4.41E-16), and in Swedes HLA-B*08:01 was the primary risk allele (OR = 4.24, P

Human leukocyte antigen (HLA) class I-specific killer-cell immunoglobulin-like receptors (KIR) regulate natural killer (NK) cell function in eliminating malignancy. Breast cancer (BC) patients exhibit reduced NK-cytotoxicity in peripheral blood. To test the hypothesis that certain KIR-HLA combinations impairing NK-cytotoxicity predispose to BC risk, we analyzed KIR and HLA polymorphisms in 162 women with BC and 278 controls. KIR-Bx genotypes increased significantly in BC than controls (83.3% vs. 71.9%, OR 1.95), and the increase was more pronounced in advanced-cancer (OR 5.3). No difference was observed with inhibitory KIR (iKIR) and HLA-ligand combinations. The activating KIR (aKIR) and HLA-ligand combinations, 2DS1 + C2 (OR 2.98) and 3DS1 + Bw4 (OR 2.6), were significantly increased in advanced-BC. All patients with advanced-cancer carrying 2DS1 + C2 or 3DS1 + Bw4 also have their iKIR counterparts 2DL1 and 3DL1, respectively. Contrarily, the 2DL1 + C2 and 3DL1 + Bw4 pairs without their aKIR counterparts are significantly higher in controls. These data suggest that NK cells expressing iKIR to the cognate HLA-ligands in the absence of putative aKIR counterpart are instrumental in antitumor response. These data provide a new framework for improving the utility of genetic risk scores for individualized surveillance.

Killer cell immunoglobulin-like receptors (KIR) regulate immune responses in NK and CD8+ T cells via interaction with HLA ligands. KIR genes, including KIR2DS1, KIR3DL1, and KIR3DS1 have previously been implicated in psoriasis susceptibility. However, these previous studies were constrained to small sample sizes, in part due to the time and expense required for direct genotyping of KIR genes. Here, we implemented KIR*IMP to impute KIR copy number from single-nucleotide polymorphisms (SNPs) on chromosome 19 in the discovery cohort (n=11,912) from the PAGE consortium, University of California San Francisco, and the University of Dundee, and in a replication cohort (n=66,357) from Kaiser Permanente Northern California. Stratified multivariate logistic regression that accounted for patient ancestry and high-risk HLA alleles revealed that KIR2DL2 copy number was significantly associated with psoriasis in the discovery cohort (p ≤ 0.05). The KIR2DL2 copy number association was replicated in the Kaiser Permanente replication cohort. This is the first reported association of KIR2DL2 copy number with psoriasis and highlights the importance of KIR genetics in the pathogenesis of psoriasis.

Immune dysfunction plays a role in the development of Parkinson disease (PD). NK cells regulate immune functions and are modulated by killer cell immunoglobulin-like receptors (KIR). KIR are expressed on the surface of NK cells and interact with HLA class I ligands on the surface of all nucleated cells. We investigated KIR-allelic polymorphism to interrogate the role of NK cells in PD. We sequenced KIR genes from 1314 PD patients and 1978 controls using next-generation methods and identified KIR genotypes using custom bioinformatics. We examined associations of KIR with PD susceptibility and disease features, including age at disease onset and clinical symptoms. We identified two KIR3DL1 alleles encoding highly expressed inhibitory receptors associated with protection from PD clinical features in the presence of their cognate ligand: KIR3DL1*015/HLA-Bw4 from rigidity (p c = 0.02, odds ratio [OR] = 0.39, 95% confidence interval [CI] 0.23-0.69) and KIR3DL1*002/HLA-Bw4i from gait difficulties (p c = 0.05, OR = 0.62, 95% CI 0.44-0.88), as well as composite symptoms associated with more severe disease. We also developed a KIR3DL1/HLA interaction strength metric and found that weak KIR3DL1/HLA interactions were associated with rigidity (pc = 0.05, OR = 9.73, 95% CI 2.13-172.5). Highly expressed KIR3DL1 variants protect against more debilitating symptoms of PD, strongly implying a role of NK cells in PD progression and manifestation.

While the relationship of protective human leukocyte antigen (HLA) class I alleles and HIV progression is well defined, the interaction of HLA-mediated protection and CD8 T-cell exhaustion is less well characterized. To gain insight into the influence of HLA-B*57:01 on the deterioration of CD8 T-cell responses during HIV infection in the absence of antiretroviral treatment, we compared HLA-B*57:01-restricted HIV-specific CD8 T-cell responses to responses restricted by other HLA class I alleles longitudinally after control of peak viremia. Detailed characterization of polyfunctionality, differentiation phenotypes, transcription factor, and inhibitory receptor expression revealed progression of CD8 T-cell exhaustion over the course of the infection in both patient groups. However, early effects on the phenotype of the total CD8 T-cell population were apparent only in HLA-B*57-negative patients. The HLA-B*57:01-restricted, HIV epitope-specific CD8 T-cell responses showed beneficial functional patterns and significantly lower frequencies of inhibitory receptor expression, i.e., PD-1 and coexpression of PD-1 and TIGIT, within the first year of infection. Coexpression of PD-1 and TIGIT was correlated with clinical markers of disease progression and declining percentages of the T-bethi Eomesdim CD8 T-cell population. In accordance with clinical and immunological deterioration in the HLA-B*57:01 group, the difference in PD-1 and TIGIT receptor expression did not persist to later stages of the disease.IMPORTANCE Given the synergistic nature of TIGIT and PD-1, the coexpression of those inhibitory receptors should be considered when evaluating T-cell pathogenesis, developing immunomodulatory therapies or vaccines for HIV, and when using immunotherapy or vaccination for other causes in HIV-infected patients. HIV-mediated T-cell exhaustion influences the patient´s disease progression, immune system and subsequently non-AIDS complications, and efficacy of vaccinations against other pathogens. Consequently, the possibilities of interfering with exhaustion are numerous. Expanding the use of immunomodulatory therapies to include HIV treatment depends on information about possible targets and their role in the deterioration of the immune system. Furthermore, the rise of immunotherapies against cancer and elevated cancer incidence in HIV-infected patients together increase the need for detailed knowledge of T-cell exhaustion and possible interactions. A broader approach to counteract immune exhaustion to alleviate complications and improve efficacy of other vaccines also promises to increase patients' health and quality of life.

The study objective was to test the hypothesis that having histocompatible children increases the risk of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), possibly by contributing to the persistence of fetal cells acquired during pregnancy. We conducted a case control study using data from the UC San Francisco Mother Child Immunogenetic Study and studies at the Inova Translational Medicine Institute. We imputed human leukocyte antigen (HLA) alleles and minor histocompatibility antigens (mHags). We created a variable of exposure to histocompatible children. We estimated an average sequence similarity matching (SSM) score for each mother based on discordant mother-child alleles as a measure of histocompatibility. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals. A total of 138 RA, 117 SLE, and 913 control mothers were analyzed. Increased risk of RA was associated with having any child compatible at HLA-B (OR 1.9; 1.2-3.1), DPB1 (OR 1.8; 1.2-2.6) or DQB1 (OR 1.8; 1.2-2.7). Compatibility at mHag ZAPHIR was associated with reduced risk of SLE among mothers carrying the HLA-restriction allele B*07:02 (n = 262; OR 0.4; 0.2-0.8). Our findings support the hypothesis that mother-child histocompatibility is associated with risk of RA and SLE.

The study objective was to test the hypothesis that having histocompatible children increases the risk of rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), possibly by contributing to the persistence of fetal cells acquired during pregnancy. We conducted a case control study using data from the UC San Francisco Mother Child Immunogenetic Study and studies at the Inova Translational Medicine Institute. We imputed human leukocyte antigen (HLA) alleles and minor histocompatibility antigens (mHags). We created a variable of exposure to histocompatible children. We estimated an average sequence similarity matching (SSM) score for each mother based on discordant mother-child alleles as a measure of histocompatibility. We used logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals. A total of 138 RA, 117 SLE, and 913 control mothers were analyzed. Increased risk of RA was associated with having any child compatible at HLA-B (OR 1.9; 1.2-3.1), DPB1 (OR 1.8; 1.2-2.6) or DQB1 (OR 1.8; 1.2-2.7). Compatibility at mHag ZAPHIR was associated with reduced risk of SLE among mothers carrying the HLA-restriction allele B*07:02 (n = 262; OR 0.4; 0.2-0.8). Our findings support the hypothesis that mother-child histocompatibility is associated with risk of RA and SLE.

BackgroundThe major histocompatibility complex class I (MHC-I) molecule is a protein complex that displays intracellular peptides to T cells, allowing the immune system to recognize and destroy infected or cancerous cells. MHC-I is composed of a highly polymorphic HLA-encoded alpha chain that binds the peptide and a Beta-2-microglobulin (B2M) protein that acts as a stabilizing scaffold. HLA mutations have been implicated as a mechanism of immune evasion during tumorigenesis, and B2M is considered a tumor suppressor gene. However, the implications of somatic HLA and B2M mutations have not been fully explored in the context of antigen presentation via the MHC-I molecule during tumor development. To understand the effect that B2M and HLA MHC-I molecule mutations have on mutagenesis, we analyzed the accumulation of mutations in patients from The Cancer Genome Atlas according to their MHC-I molecule mutation status.ResultsSomatic B2M and HLA mutations in microsatellite stable tumors were associated with higher overall mutation burden and a larger fraction of HLA-binding neoantigens when compared to B2M and HLA wild type tumors. B2M and HLA mutations were highly enriched in patients with microsatellite instability. B2M mutations tended to occur relatively early during patients' respective tumor development, whereas HLA mutations were either early or late events. In addition, B2M and HLA mutated patients had higher levels of immune infiltration by natural killer and CD8+ T cells and higher levels of cytotoxicity.ConclusionsOur findings add to a growing body of evidence that somatic B2M and HLA mutations are a mechanism of immune evasion by demonstrating that such mutations are associated with a higher load of neoantigens that should be presented via MHC-I.

HLA class I and KIR sequences were determined for Dogon, Fulani, and Baka populations of western Africa, Mbuti of central Africa, and Datooga, Iraqw, and Hadza of eastern Africa. Study of 162 individuals identified 134 HLA class I alleles (41 HLA-A, 60 HLA-B, and 33 HLA-C). Common to all populations are three HLA-C alleles (C1+C*07:01, C1+C*07:02, and C2+C*06:02) but no HLA-A or -B Unexpectedly, no novel HLA class I was identified in these previously unstudied and anthropologically distinctive populations. In contrast, of 227 KIR detected, 22 are present in all seven populations and 28 are novel. A high diversity of HLA A-C-B haplotypes was observed. In six populations, most haplotypes are represented just once. But in the Hadza, a majority of haplotypes occur more than once, with 2 having high frequencies and 10 having intermediate frequencies. The centromeric (cen) part of the KIR locus exhibits an even balance between cenA and cenB in all seven populations. The telomeric (tel) part has an even balance of telA to telB in East Africa, but this changes across the continent to where telB is vestigial in West Africa. All four KIR ligands (A3/11, Bw4, C1, and C2) are present in six of the populations. HLA haplotypes of the Iraqw and Hadza encode two KIR ligands, whereas the other populations have an even balance between haplotypes encoding one and two KIR ligands. Individuals in these African populations have a mean of 6.8-8.4 different interactions between KIR and HLA class I, compared with 2.9-6.5 for non-Africans.

DNA sequence-based typing at the HLA-A, -B, -C, -DPB1, -DQA1, -DQB1, and -DRB1 loci was performed on 496 healthy adult donors from San Diego, California, to characterize allele frequencies in support of studies of T cell responses to common allergens. Deviations from Hardy Weinberg proportions were detected at each locus except A and C. Several alleles were found in more than 15% of individuals, including the class II alleles DPB1∗02:01, DPB1∗04:01, DQA1∗01:02, DQA1∗05:01, DQB1∗03:01, and the class I allele A∗02:01. Genotype data will be available in the Allele Frequencies Net Database (AFND 3562).

HLA-B*57 control of HIV involves enhanced CD8+ T cell responses against infected cells, but extensive heterogeneity exists in the level of HIV control among B*57+ individuals. Using whole-genome sequencing of untreated B*57+ HIV-1-infected controllers and noncontrollers, we identified a single variant (rs643347A/G) encoding an isoleucine-to-valine substitution at position 47 (I47V) of the inhibitory killer cell immunoglobulin-like receptor KIR3DL1 as the only significant modifier of B*57 protection. The association was replicated in an independent cohort and across multiple outcomes. The modifying effect of I47V was confined to B*57:01 and was not observed for the closely related B*57:03. Positions 2, 47, and 54 tracked one another nearly perfectly, and 2 KIR3DL1 allotypes differing only at these 3 positions showed significant differences in binding B*57:01 tetramers, whereas the protective allotype showed lower binding. Thus, variation in an immune NK cell receptor that binds B*57:01 modifies its protection. These data highlight the exquisite specificity of KIR-HLA interactions in human health and disease.

DNA sequence-based typing at the HLA-A, -B, -C, -DPB1, -DQA1, -DQB1, and -DRB1 loci was performed on 714 healthy adult blood bank donors from Colombo, Sri Lanka, to characterize allele frequencies in support of studies on T cell immunity against pathogens, including Dengue virus. Deviations from Hardy Weinberg proportions were not detected at any locus. Several alleles were found in >30% of individuals, including the class II alleles DPB1 * 04:01, DPB1 * 02:01, DQB1 * 06:01 and DRB1 * 07:01, and the class I alleles A * 33:03 and A * 24:02. Genotype data will be available in the Allele Frequencies Net Database.

DNA sequence-based typing at the HLA-A, -B, -C, -DPB1, -DQA1, -DQB1, and -DRB1 loci was performed on anonymized samples provided by 339 healthy adult blood bank donors in Managua, Nicaragua. The purpose of the study was to characterize allele frequencies in the local population to support studies of T cell immunity against pathogens, including Dengue virus. Deviations from Hardy Weinberg proportions were detected for all class II loci (HLA-DPB1, -DQA1, -DQB1 and -DRB1), and at the class I C locus, but not at the class I A and B loci. The genotype data will be available in the Allele Frequencies Net Database.

Patient-derived HIV-1 subtype B Nef clones downregulate HLA-A more efficiently than HLA-B. However, it remains unknown whether this property is common to Nef proteins across primate lentiviruses and how antiviral immune responses may be affected. We examined 263 Nef clones from diverse primate lentiviruses including different pandemic HIV-1 group M subtypes for their ability to downregulate major histocompatibility complex class A (MHC-A) and MHC-B from the cell surface. Though lentiviral Nef proteins differed markedly in their absolute MHC-A and MHC-B downregulation abilities, all lentiviral Nef lineages downregulated MHC-A, on average, 11 to 32% more efficiently than MHC-B. Nef genotype/phenotype analyses in a cohort of HIV-1 subtype C-infected patients (n = 168), together with site-directed mutagenesis, revealed Nef position 9 as a subtype-specific determinant of differential HLA-A versus HLA-B downregulation activity. Nef clones harboring nonconsensus variants at codon 9 downregulated HLA-B (though not HLA-A) significantly better than those harboring the consensus sequence at this site, resulting in reduced recognition of infected target cells by HIV-1-specific CD8+ effector cells in vitro Among persons expressing protective HLA class I alleles, carriage of Nef codon 9 variants was also associated with reduced ex vivo HIV-specific T cell responses. Our results demonstrate that Nef's inferior ability to downregulate MHC-B compared to that of MHC-A is conserved across primate lentiviruses and suggest that this property influences antiviral cellular immune responses.IMPORTANCE Primate lentiviruses encode the Nef protein that plays an essential role in establishing persistent infection in their respective host species. Nef interacts with the cytoplasmic region of MHC-A and MHC-B molecules and downregulates them from the infected cell surface to escape recognition by host cellular immunity. Using a panel of Nef alleles isolated from diverse primate lentiviruses including pandemic HIV-1 group M subtypes, we demonstrate that Nef proteins across all lentiviral lineages downregulate MHC-A approximately 20% more effectively than MHC-B. We further identify a naturally polymorphic site at Nef position 9 that contributes to the MHC-B downregulation function in HIV-1 subtype C and show that carriage of Nef variants with enhanced MHC-B downregulation ability is associated with reduced breadth and magnitude of MHC-B-restricted cellular immune responses in HIV-infected individuals. Our study underscores an evolutionarily conserved interaction between lentiviruses and primate immune systems that may contribute to pathogenesis.

To expand upon our previous observation that HIV-1 Gag-specific IgG antibodies were highest in HIV controllers not carrying HLA-B*57:01, we analysed these antibodies in a larger cohort of viremic controllers (VCs) or elite controllers (ECs) considering carriage of ‘protective’ HLA-B alleles. HIV-1 p24-specific IgG1 and IgG2 antibodies were higher only in HLA-B*57:01− VCs but there were no differences in ECs. Associations of HIV-1 gp140-specific IgG antibodies with HLA-B*57:01 carriage were inconsistent amongst VCs and ECs.

Despite a poor toxicity profile, zidovudine supersedes abacavir (ABC) as an alternative first-line agent in most international treatment guidelines because of concerns about HLA-B*57:01-related ABC-hypersensitivity. We detected one case of HLA-B*57:01 carriage among 513 HIV-infected individuals in Uganda, which, in combination with previous reports, supports the safety of ABC in the region.

ObjectiveTo investigate whether a child's genotype affects a mother's risk of rheumatoid arthritis (RA) beyond the risk associated with her genotype and to test whether exposure to fetal alleles inherited from the father increases risk of RA among mothers without risk alleles.MethodsA case-control study was conducted among 1165 mothers (170 cases/995 controls) and their respective 1482 children. We tested the association between having any child with alleles encoding amino acids (AAs) associated with RA including the 'shared epitope' (SE) and DERAA AA sequences at positions 70-74; AA valine, lysine and alanine at positions 11, 71 and 74 of HLA-DRB1; aspartic acid at position 9 of HLA-B and phenylalanine at position 9 of DPB1. We used logistic regression models to estimate OR and 95% CI for each group of alleles, adjusting for maternal genotype and number of live births.ResultsWe found increased risk of RA among mothers who had any child with SE (OR 3.0; 95% CI 2.0 to 4.6); DERAA (OR 1.7; 95% CI 1.1 to 2.6); or valine (OR 2.3; 95% CI 1.6 to 3.5), lysine (OR 2.3; 95% CI 1.5 to 3.4) and alanine (OR 2.8; 95% CI 1.2 to 6.4) at DRB1 positions 11, 71 and 74, respectively. Among non-carrier mothers, increased risk of RA was associated with having children who carried DERAA (OR 1.7; 95% CI 1.0 to 2.7) and alleles encoding lysine at DRB1 position 71 (OR 2.3; 95% CI 1.5 to 4.8).ConclusionFindings support the hypothesis that a child's genotype can contribute independently to risk of RA among mothers.

Chronic lung allograft dysfunction (CLAD) is linked to rejection and limits survival following lung transplantation. HLA-Bw4 recipients of HLA-Bw6 grafts have enhanced host-versus-graft (HVG) natural killer (NK) cell activity mediated by killer cell immunoglobulin-like receptor (KIR)3DL1 ligand. Because NK cells may promote tolerance by depleting antigen-presenting cells, we hypothesized improved outcomes for HLA-Bw4 recipients of HLA-Bw6 grafts. We evaluated differences in acute cellular rejection and CLAD-free survival across 252 KIR3DL1+ recipients from University of California, San Francisco (UCSF). For validation, we assessed survival and freedom from bronchiolitis obliterans syndrome (BOS), retransplantation, or death in 12 845 non-KIR typed recipients from the United Network for Organ Sharing (UNOS) registry. Cox proportional hazards models were adjusted for age, gender, ethnicity, transplant type, and HLA mismatching. HVG-capable subjects in the UCSF cohort had a decreased risk of CLAD or death (hazard ratio [HR] 0.57, 95% confidence interval [CI] 0.36-0.88) and decreased early lymphocytic bronchitis. The HVG effect was not significant in subjects with genotypes predicting low KIR3DL1 expression. In the UNOS cohort, HVG-capable subjects had a decreased risk of BOS, retransplant, or death (HR 0.95, 95% CI 0.91-0.99). Survival improved with the higher-affinity Bw4-80I ligand and in Bw4 homozygotes. Improved outcomes in HVG-capable recipients are consistent with a protective NK cell role. Augmentation of NK activity could supplement current immunosuppression techniques.

Some HIV-1-infected patients develop broad and potent HIV-1 neutralizing antibodies (bNAbs) that when passively transferred to mice or macaques can treat or prevent infection. However, bNAbs typically fail to neutralize coexisting autologous viruses due to antibody-mediated selection against sensitive viral strains. We describe an HIV-1 controller expressing HLA-B57*01 and HLA-B27*05 who maintained low viral loads for 30 years after infection and developed broad and potent serologic activity against HIV-1. Neutralization was attributed to three different bNAbs targeting nonoverlapping sites on the HIV-1 envelope trimer (Env). One of the three, BG18, an antibody directed against the glycan-V3 portion of Env, is the most potent member of this class reported to date and, as revealed by crystallography and electron microscopy, recognizes HIV-1 Env in a manner that is distinct from other bNAbs in this class. Single-genome sequencing of HIV-1 from serum samples obtained over a period of 9 years showed a diverse group of circulating viruses, 88.5% (31 of 35) of which remained sensitive to at least one of the temporally coincident autologous bNAbs and the individual's serum. Thus, bNAb-sensitive strains of HIV-1 coexist with potent neutralizing antibodies that target the virus and may contribute to control in this individual. When administered as a mix, the three bNAbs controlled viremia in HIV-1YU2-infected humanized mice. Our finding suggests that combinations of bNAbs may contribute to control of HIV-1 infection.

We investigated the role of the KIR loci and their HLA class I ligands in a large cohort of African American multiple sclerosis (MS) patients (N=907) and controls (N=1456). No significant differences in carrier frequencies for any KIR locus or haplotype were observed between cases and controls. However, examination of KIR in the context of their cognate HLA ligands revealed a strong protective effect for KIR3DL1 in combination with HLA-A and -B alleles bearing the Bw4 motif (P=10(-8); odds ratio (OR)=0.60, confidence interval (CI)=0.50-0.71) and the Bw4 ligand alone (P

ObjectiveThe human major histocompatibility complex class I chain-related gene A (MICA) controls the immune process by balancing activities of  natural killer cells, γδ T cells and αβ CD8 T cells, and immunosuppressive CD4 T cells. MICA is located near HLA-B on chromosome 6. Recent genomewide association studies indicate that genes most strongly linked to ankylosing spondylitis (AS) susceptibility come from the region containing HLA-B and MICA. While HLA-B27 is a well-known risk genetic marker for AS, the potential effect of linkage disequilibrium (LD) shields any associations of genes around HLA-B with AS. The aim of this study was to investigate a novel independent genetic association of MICA to AS.MethodsWe examined 1543 AS patients and 1539 controls from two ethnic populations by sequencing MICA and genotyping HLA-B alleles. Initially, 1070 AS patients and 1003 controls of European ancestry were used as a discovery cohort, followed by a confirmation cohort of 473 Han Chinese AS patients and 536 controls. We performed a stratified analysis based on HLA-B27 carrier status. We also conducted logistic regression with a formal interaction term.ResultsSequencing of MICA identified that MICA*007:01 is a significant risk allele for AS in both Caucasian and Han Chinese populations, and that MICA*019 is a major risk allele in Chinese AS patients. Conditional analysis of MICA alleles on HLA-B27 that unshielded LD effect confirmed associations of the MICA alleles with AS.ConclusionsParallel with HLA-B27, MICA confers strong susceptibility to AS in US white and Han Chinese populations.

MHC class I polymorphisms are known to influence outcomes in a number of infectious diseases, cancers, and inflammatory diseases. Human MHC class I H chains are encoded by the HLA-A, HLA-B, and HLA-C genes. These genes are highly polymorphic, with the HLA-B locus being the most variable. Each HLA class I protein binds to a distinct set of peptide Ags, which are presented to CD8(+) T cells. HLA-disease associations have been shown in some cases to link to the peptide-binding characteristics of individual HLA class I molecules. In this study, we show that polymorphisms at the HLA-B locus profoundly influence the assembly characteristics of HLA-B molecules and the stabilities of their peptide-deficient forms. In particular, dependence on the assembly factor tapasin is highly variable, with frequent occurrence of strongly tapasin-dependent or independent allotypes. Several polymorphic HLA-B residues located near the C-terminal end of the peptide are key determinants of tapasin-independent assembly. In vitro refolded forms of tapasin-independent allotypes assemble more readily with peptides compared to tapasin-dependent allotypes that belong to the same supertype, and, during refolding, reduced aggregation of tapasin-independent allotypes is observed. Paradoxically, in HIV-infected individuals, greater tapasin-independent HLA-B assembly confers more rapid progression to death, consistent with previous findings that some HLA-B allotypes shown to be tapasin independent are associated with rapid progression to multiple AIDS outcomes. Together, these findings demonstrate significant variations in the assembly of HLA-B molecules and indicate influences of HLA-B-folding patterns upon infectious disease outcomes.

Viral escape from HIV-1-specific CD8(+) T cells has been demonstrated in numerous studies previously. However, the qualitative features driving the emergence of mutations within epitopes are still unclear. In this study, we aimed to distinguish whether specific functional characteristics of HLA-B*5701-restricted CD8(+) T cells influence the emergence of mutations in high-risk progressors (HRPs) versus low-risk progressors (LRPs). Single-genome sequencing was performed to detect viral mutations (variants) within seven HLA-B*5701-restricted epitopes in Gag (n = 4) and Nef (n = 3) in six untreated HLA-B*5701 subjects followed from early infection up to 7 y. Several well-characterized effector markers (IFN-γ, IL-2, MIP-1β, TNF, CD107a, and perforin) were identified by flow cytometry following autologous (initial and emerging variant/s) epitope stimulations. This study demonstrates that specific functional attributes may facilitate the outgrowth of mutations within HLA-B*5701-restricted epitopes. A significantly lower fraction of IL-2-producing cells and a decrease in functional avidity and polyfunctional sensitivity were evident in emerging epitope variants compared with the initial autologous epitopes. Interestingly, the HRPs mainly drove these differences, whereas the LRPs maintained a directed and maintained functional response against emerging epitope variants. In addition, LRPs induced improved cell-cycle progression and perforin upregulation after autologous and emerging epitope variant stimulations in contrast to HRPs. The maintained quantitative and qualitative features of the CD8(+) T cell responses in LRPs toward emerging epitope variants provide insights into why HLA-B*5701 subjects have different risks of HIV-1 disease progression.

UnlabelledHLA-B*57:01 and HLA-B*57:03, the most prevalent HLA-B*57 subtypes in Caucasian and African populations, respectively, are the HLA alleles most protective against HIV disease progression. Understanding the mechanisms underlying this immune control is of critical importance, yet they remain unclear. Unexplained differences are observed in the impact of the dominant cytotoxic T lymphocyte (CTL) response restricted by HLA-B*57:01 and HLA-B*57:03 in chronic infection on the Gag epitope KAFSPEVIPMF (KF11; Gag 162 to 172). We previously showed that the HLA-B*57:03-KF11 response is associated with a >1-log-lower viral setpoint in C clade virus infection and that this response selects escape mutants within the epitope. We first examined the relationship of KF11 responses in B clade virus-infected subjects with HLA-B*57:01 to immune control and observed that a detectable KF11 response was associated with a >1-log-higher viral load (P = 0.02). No evidence of HLA-B*57:01-KF11-associated selection pressure was identified in previous comprehensive analyses of >1,800 B clade virus-infected subjects. We then studied a B clade virus-infected cohort in Barbados, where HLA-B*57:03 is highly prevalent. In contrast to findings for B clade virus-infected subjects expressing HLA-B*57:01, we observed strong selection pressure driven by the HLA-B*57:03-KF11 response for the escape mutation S173T. This mutation reduces recognition of virus-infected cells by HLA-B*57:03-KF11 CTLs and is associated with a >1-log increase in viral load in HLA-B*57:03-positive subjects (P = 0.009). We demonstrate functional constraints imposed by HIV clade relating to the residue at Gag 173 that explain the differential clade-specific escape patterns in HLA-B*57:03 subjects. Further studies are needed to evaluate the role of the KF11 response in HLA-B*57:01-associated HIV disease protection.ImportanceHLA-B*57 is the HLA class I molecule that affords the greatest protection against disease progression in HIV infection. Understanding the key mechanism(s) underlying immunosuppression of HIV is of importance in guiding therapeutic and vaccine-related approaches to improve the levels of HIV control occurring in nature. Numerous mechanisms have been proposed to explain the HLA associations with differential HIV disease outcome, but no consensus exists. These studies focus on two subtypes of HLA-B*57 prevalent in Caucasian and African populations, HLA-B*57:01 and HLA-B*57:03, respectively. These alleles appear equally protective against HIV disease progression. The CTL epitopes presented are in many cases identical, and the dominant response in chronic infection in each case is to the Gag epitope KF11. However, there the similarity ends. This study sought to better understand the reasons for these differences and what they teach us about which immune responses contribute to immune control of HIV infection.

ObjectiveHIV controllers demonstrate high rates of spontaneous clearance of hepatitis C virus (HCV) infection. The objective of this study was to evaluate the role of human leukocyte antigen (HLA) B*57 and other genetic polymorphisms on HCV clearance in HIV controllers.DesignThis is a prospective cohort study.MethodsPatients in the Study of the Consequences of Protease Inhibitor Era (SCOPE) were tested for anti-HCV using enzyme immunoassay (EIA3) and HCV RNA using discriminatory HCV transcription-mediated amplification assay (Norvatis). We compared the proportion of HIV controllers and noncontrollers demonstrating HCV clearance and fitted multivariable Poisson regression models with robust standard errors to estimate adjusted prevalence ratios (APRs) and assessed genetic and immunologic predictors of HCV clearance.ResultsOf 279 HIV/HCV seropositive individuals, 48 were HIV controllers. HIV controllers compared to HIV noncontrollers, were significantly more likely to have HLA B*57 (33 vs. 10%, P

BackgroundThe HLA (human leukocyte antigen) molecules that present pathogen-derived epitopes to T cells are highly diverse. Correspondingly, many pathogens such as HIV evolve epitope variants in order to evade immune recognition. In contrast, another persistent human pathogen, Mycobacterium tuberculosis, has highly conserved epitope sequences. This raises the question whether there is also a difference in the ability of these pathogens' epitopes to bind diverse HLA alleles, referred to as an epitope's binding promiscuity. To address this question, we compared the in silico HLA binding promiscuity of T cell epitopes from pathogens with distinct infection strategies and outcomes of human exposure.MethodsWe used computer algorithms to predict the binding affinity of experimentally-verified microbial epitope peptides to diverse HLA-DR, HLA-A and HLA-B alleles. We then analyzed binding promiscuity of epitopes derived from HIV and M. tuberculosis. We also analyzed promiscuity of epitopes from Streptococcus pyogenes, which is known to exhibit epitope diversity, and epitopes of Bacillus anthracis and Clostridium tetani toxins, as these bacteria do not depend on human hosts for their survival or replication, and their toxin antigens are highly immunogenic human vaccines.ResultsWe found that B. anthracis and C. tetani epitopes were the most promiscuous of the group that we analyzed. However, there was no consistent difference or trend in promiscuity in epitopes contained in HIV, M. tuberculosis, and S. pyogenes.ConclusionsOur results show that human pathogens with distinct immune evasion strategies and epitope diversities exhibit equivalent levels of T cell epitope promiscuity. These results indicate that differences in epitope promiscuity do not account for the observed differences in epitope variation and conservation.

We have performed a meta-analysis of the major-histocompatibility-complex (MHC) region in systemic lupus erythematosus (SLE) to determine the association with both SNPs and classical human-leukocyte-antigen (HLA) alleles. More specifically, we combined results from six studies and well-known out-of-study control data sets, providing us with 3,701 independent SLE cases and 12,110 independent controls of European ancestry. This study used genotypes for 7,199 SNPs within the MHC region and for classical HLA alleles (typed and imputed). Our results from conditional analysis and model choice with the use of the Bayesian information criterion show that the best model for SLE association includes both classical loci (HLA-DRB1(∗)03:01, HLA-DRB1(∗)08:01, and HLA-DQA1(∗)01:02) and two SNPs, rs8192591 (in class III and upstream of NOTCH4) and rs2246618 (MICB in class I). Our approach was to perform a stepwise search from multiple baseline models deduced from a priori evidence on HLA-DRB1 lupus-associated alleles, a stepwise regression on SNPs alone, and a stepwise regression on HLA alleles. With this approach, we were able to identify a model that was an overwhelmingly better fit to the data than one identified by simple stepwise regression either on SNPs alone (Bayes factor [BF] > 50) or on classical HLA alleles alone (BF > 1,000).

HLA-B*5701 is the host factor most strongly associated with slow HIV-1 disease progression, although rates can vary within this group. Underlying mechanisms are not fully understood but likely involve both immunological and virological dynamics. The present study investigated HIV-1 in vivo evolution and epitope-specific CD8(+) T cell responses in six HLA-B*5701 patients who had not received antiretroviral treatment, monitored from early infection for up to 7 years. The subjects were classified as high-risk progressors (HRPs) or low-risk progressors (LRPs) based on baseline CD4(+) T cell counts. Dynamics of HIV-1 Gag p24 evolution and multifunctional CD8(+) T cell responses were evaluated by high-resolution phylogenetic analysis and polychromatic flow cytometry, respectively. In all subjects, substitutions occurred more frequently in flanking regions than in HLA-B*5701-restricted epitopes. In LRPs, p24 sequence diversity was significantly lower; sequences exhibited a higher degree of homoplasy and more constrained mutational patterns than HRPs. The HIV-1 intrahost evolutionary rate was also lower in LRPs and followed a strict molecular clock, suggesting neutral genetic drift rather than positive selection. Additionally, polyfunctional CD8(+) T cell responses, particularly to TW10 and QW9 epitopes, were more robust in LRPs, who also showed significantly higher interleukin-2 (IL-2) production in early infection. Overall, the findings indicate that HLA-B*5701 patients with higher CD4 counts at baseline have a lower risk of HIV-1 disease progression because of the interplay between specific HLA-linked immune responses and the rate and mode of viral evolution. The study highlights the power of a multidisciplinary approach, integrating high-resolution evolutionary and immunological data, to understand mechanisms underlying HIV-1 pathogenesis.

Mutations within cytotoxic T lymphocyte (CTL) epitopes impair T cell recognition, but escape mutations arising in flanking regions that alter antigen processing have not been defined in natural human infections. In human histocompatibility leukocyte antigen (HLA)-B57+ HIV-infected persons, immune selection pressure leads to a mutation from alanine to proline at Gag residue 146 immediately preceding the NH2 terminus of a dominant HLA-B57-restricted epitope, ISPRTLNAW. Although N-extended wild-type or mutant peptides remained well-recognized, mutant virus-infected CD4 T cells failed to be recognized by the same CTL clones. The A146P mutation prevented NH2-terminal trimming of the optimal epitope by the endoplasmic reticulum aminopeptidase I. These results demonstrate that allele-associated sequence variation within the flanking region of CTL epitopes can alter antigen processing. Identifying such mutations is of major relevance in the construction of vaccine sequences.

The killer cell inhibitory receptors (KIR) of human natural killer (NK) cells recognize human leukocyte antigen class I molecules and inhibit NK cell cytotoxicity through their interaction with protein tyrosine phosphatases (PTP). Here, we report that KIR recognition of class I ligands inhibits distal signaling events and ultimately NK cell cytotoxicity by blocking the association of an adaptor protein (pp36) with phospholipase C-gamma in NK cells. In addition, we demonstrate that pp36 can serve as a substrate in vitro for the KIR-associated PTP, PTP-1C (also called SHP-1), and that recognition of class I partially disrupts tyrosine phosphorylation of NK cell proteins, providing evidence for KIR-induced phosphatase activity.

The killer cell inhibitory receptors (KIR) of human natural killer (NK) cells recognize human leukocyte antigen class I molecules and inhibit NK cell cytotoxicity through their interaction with protein tyrosine phosphatases (PTP). Here, we report that KIR recognition of class I ligands inhibits distal signaling events and ultimately NK cell cytotoxicity by blocking the association of an adaptor protein (pp36) with phospholipase C-gamma in NK cells. In addition, we demonstrate that pp36 can serve as a substrate in vitro for the KIR-associated PTP, PTP-1C (also called SHP-1), and that recognition of class I partially disrupts tyrosine phosphorylation of NK cell proteins, providing evidence for KIR-induced phosphatase activity.

Although inhibition of natural killer (NK) cell-mediated lysis by the class I HLA molecules of target cells is an established phenomenon, knowledge of the features of class I molecules which induce this effect remains rudimentary. Using class I alleles HLA-B*1502 and B*1513 which differ only at residues 77-83 which define the Bw4 and Bw6 serological epitopes, we tested the hypothesis that the presence of the Bw4 epitope on class I molecules determines recognition by NKB1+ NK cells. HLA-B*1513 possesses the Bw4 epitope, whereas B*1502 has the Bw6 epitope. Lysis by NKB1+ NK cell clones of transfected target cells expressing B*1513 as the only HLA-A, -B, or -C molecule was inhibited, whereas killing of transfectants expressing B*1502 was not. Addition of an an anti-NKB1 monoclonal antibody reconstituted lysis of the targets expressing B*1513, but did not affect killing of targets bearing B*1502. The inhibitory effect of B*1513 could be similarly prevented by the addition of an anti-class I monoclonal antibody. These results show that the presence of the Bw4 epitope influences recognition of HLA-B molecules by NK cells that express NKB1, and suggest that the NKB1 molecule may act as a receptor for Bw4+ HLA-B alleles. Sequences outside of the Bw4 region must also affect recognition by NKB1+ NK cells, because lysis of transfectants expressing HLA-A*2403 or A*2501, which possess the Bw4 epitope but are in other ways substantially different from HLA-B molecules, was not increased by addition of the anti-NKB1 antibody. Asparagine 86, the single site of N-linked glycosylation on class I molecules, is in close proximity to the Bw4/Bw6 region. The glycosylation site of the Bw4-positive molecule B*5801 was mutated, and the mutant molecules tested for inhibition of NKB1+ NK cells. Inhibition that could be reversed by addition of the anti-NKB1 monoclonal antibody was observed, showing the presence of the carbohydrate moiety is not essential for class I recognition by NKB1+ NK cell clones.

Natural killer (NK) cells kill normal and transformed hematopoietic cells that lack expression of major histocompatibility complex (MHC) class I antigens. Lysis of HLA-negative Epstein Barr virus-transformed B lymphoblastoid cell lines (B-LCL) by human NK cell clones can be inhibited by transfection of the target cells with certain HLA-A, -B, or -C alleles. NK cell clones established from an individual demonstrate clonal heterogeneity in HLA recognition and a single NK clone can recognize multiple alleles. We describe a potential human NK cell receptor (NKB1) for certain HLA-B alleles (e.g., HLA-B*5101 and-B*5801) identified by the mAb DX9. NKB1 is a 70-kD glycoprotein that is expressed on a subset of NK cells and NK cell clones. DX9 monoclonal antibody (mAb) specifically inhibits the interaction between NK cell clones and B-LCL targets transfected with certain HLA-B alleles, but does not affect recognition of HLA-A or HLA-C antigens. An individual NK cell clone can independently recognize B-LCL targets transfected with HLA-B or HLA-C antigens; however, DX9 mAb only affects interaction with transfectants expressing certain HLA-B alleles. These findings demonstrate the existence of NK cell receptors involved in the recognition of HLA-B and imply the presence of multiple receptors for MHC on an individual NK clone.