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1.
Hum Immunol ; 83(1): 1-9, 2022 Jan.
Article in English | MEDLINE | ID: covidwho-1719801

ABSTRACT

The class I and class II Human Leucocyte Antigens (HLA) are an integral part of the host adaptive immune system against viral infections. The characterization of HLA allele frequency in the population can play an important role in determining whether HLA antigens contribute to viral susceptibility. In this regard, global efforts are currently underway to study possible correlations between HLA alleles with the occurrence and severity of SARS-CoV-2 infection. Specifically, this study examined the possible association between specific HLA alleles and susceptibility to SARS-CoV-2 in a population from the United Arab Emirates (UAE). The frequencies of HLA class I (HLA-A, -B, and -C) and HLA class II alleles (HLA-DRB1 and -DQB1); defined using Next Generation Sequencing (NGS); from 115 UAE nationals with mild, moderate, and severe SARS-CoV-2 infection are presented here. HLA alleles and supertypes were compared between hospitalized and non-hospitalized subjects. Statistical significance was observed between certain HLA alleles and supertypes and the severity of the infection. Specifically, alleles HLA-B*51:01 and HLA-A*26:01 showed a negative association (suggestive of protection), whilst genotypes HLA-A*03:01, HLA-DRB1*15:01, and supertype B44 showed a positive association (suggestive of predisposition) to COVID-19 severity. The results support the potential use of HLA testing to differentiate between patients who require specific clinical management strategies.


Subject(s)
COVID-19/genetics , HLA Antigens/genetics , SARS-CoV-2/immunology , Adolescent , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/immunology , COVID-19/virology , Female , Gene Frequency , Genetic Predisposition to Disease , HLA Antigens/immunology , Haplotypes , Host-Pathogen Interactions , Humans , Male , Middle Aged , Protective Factors , Risk Assessment , Risk Factors , SARS-CoV-2/pathogenicity , Severity of Illness Index , United Arab Emirates , Young Adult
2.
Int J Mol Sci ; 23(5)2022 Feb 28.
Article in English | MEDLINE | ID: covidwho-1715409

ABSTRACT

We propose a new hypothesis that explains the maintenance and evolution of MHC polymorphism. It is based on two phenomena: the constitution of the repertoire of naive T lymphocytes and the evolution of the pathogen and its impact on the immune memory of T lymphocytes. Concerning the latter, pathogen evolution will have a different impact on reinfection depending on the MHC allomorph. If a mutation occurs in a given region, in the case of MHC allotypes, which do not recognize the peptide in this region, the mutation will have no impact on the memory repertoire. In the case where the MHC allomorph binds to the ancestral peptides and not to the mutated peptide, that individual will have a higher chance of being reinfected. This difference in fitness will lead to a variation of the allele frequency in the next generation. Data from the SARS-CoV-2 pandemic already support a significant part of this hypothesis and following up on these data may enable it to be confirmed. This hypothesis could explain why some individuals after vaccination respond less well than others to variants and leads to predict the probability of reinfection after a first infection depending upon the variant and the HLA allomorph.


Subject(s)
COVID-19/immunology , HLA Antigens/immunology , Polymorphism, Genetic/immunology , SARS-CoV-2/immunology , T-Lymphocytes/immunology , COVID-19/epidemiology , COVID-19/virology , Evolution, Molecular , Gene Frequency , HLA Antigens/genetics , HLA Antigens/metabolism , Humans , Immunity, Innate/genetics , Immunity, Innate/immunology , Mutation/genetics , Mutation/immunology , Pandemics , Peptides/immunology , Peptides/metabolism , Polymorphism, Genetic/genetics , SARS-CoV-2/physiology , T-Lymphocytes/cytology , T-Lymphocytes/metabolism
3.
Front Immunol ; 13: 752622, 2022.
Article in English | MEDLINE | ID: covidwho-1686481

ABSTRACT

The current coronavirus disease 2019 (COVID-19) vaccines are used to prevent viral infection by inducing neutralizing antibody in the body, but according to the existing experience of severe acute respiratory syndrome coronavirus (SARS) infection, T-cell immunity could provide a longer durable protection period than antibody. The research on SARS-CoV-2-specific T-cell epitope can provide target antigen for the development and evaluation of COVID-19 vaccines, which is conducive to obtain COVID-19 vaccine that can provide long-term protection. For screening specific T-cell epitopes, a SARS-CoV-2 S protein peptide library with a peptide length of 15 amino acids was synthesized. Through flow cytometry to detect percentage of IFN-γ+ T cells after mixed COVID-19 convalescent patients' peripheral blood mononuclear cell with peptide library, seven peptides (P77, P14, P24, P38, P48, P74, and P84) that can be recognized by the T cells of COVID-19 convalescent patients were found. After excluding the nonspecific cross-reactions with unexposed population, three SARS-CoV-2-specific T-cell potential epitopes (P38, P48, and P84) were finally screened with the positive reaction rates between 15.4% and 48.0% in COVID-19 convalescent patients. This study also provided the HLA allele information of peptide-positive-response COVID-19 convalescent patients, thus predicting the population coverage of these three potential epitopes. Some HLA alleles showed higher frequency of occurrence in COVID-19 patients than in total Chinese population but no HLA alleles related to the T-cell peptide response and the severity of COVID-19. This research provides three potential T-cell epitopes that are helpful for the design and efficacy evaluation of COVID-19 vaccines. The HLA information provided by this research supplies reference significance for subsequent research such as finding the relation of HLA genotype with disease susceptibility.


Subject(s)
COVID-19/immunology , Epitopes, T-Lymphocyte/immunology , Spike Glycoprotein, Coronavirus/immunology , Female , HLA Antigens/genetics , Humans , Male , SARS-CoV-2/immunology
4.
HLA ; 99(4): 281-312, 2022 04.
Article in English | MEDLINE | ID: covidwho-1642778

ABSTRACT

HLA is crucial for appropriate immune responses in several viral infections, as well as in severe acute respiratory syndrome coronavirus-2 (SARS CoV-2). The unpredictable nature of Coronavirus Disease 19 (COVID-19), observed in both inter-individual and inter-population level, raises the question, to what extent the HLA, as part of host genetic factors, contribute to disease susceptibility and prognosis. We aimed to identify significant HLAs, those were investigated till now, for their association with COVID-19. Three databases were searched (PubMed, Cochrane library, and Web of Science) and articles published between January 2020 and May 2021 were included for in-depth analysis. Two separate teams including four observers independently extracted the summary data, with discrepancies resolved by consensus. This study is registered with PROSPERO (CRD42021251670). Of 1278 studies identified, 36 articles were included consisting of 794,571 participants. Countries from the European region appeared in the highest number of studies and vice versa for countries from South East Asia. Among 117 significantly altered alleles, 85 (72.65%) were found to have a positive correlation with COVID-19 and 33 (27.35%) alleles were observed having a negative correlation. HLA A*02 is the most investigated allele (n = 18) and showed contradictory results. Non-classical HLA E was explored by only one study and it showed that E*01:01 is associated with severity. Both in silico and wet lab data were considered and contrasting results were found from two approaches. Although several HLAs depicted significant association, nothing conclusive could be drawn because of heterogeneity in study designs, HLA typing methods, and so forth. This systematic review shows that, though HLAs play role in COVID-19 susceptibility, severity, and mortality, more uniformly designed, interrelated studies with the inclusion of global data, for use in evidence-based medicine are needed.


Subject(s)
COVID-19 , Alleles , COVID-19/genetics , HLA Antigens/genetics , Humans , Polymorphism, Genetic , SARS-CoV-2
5.
Elife ; 102021 11 30.
Article in English | MEDLINE | ID: covidwho-1542951

ABSTRACT

T-cell receptors (TCRs) encode clinically valuable information that reflects prior antigen exposure and potential future response. However, despite advances in deep repertoire sequencing, enormous TCR diversity complicates the use of TCR clonotypes as clinical biomarkers. We propose a new framework that leverages experimentally inferred antigen-associated TCRs to form meta-clonotypes - groups of biochemically similar TCRs - that can be used to robustly quantify functionally similar TCRs in bulk repertoires across individuals. We apply the framework to TCR data from COVID-19 patients, generating 1831 public TCR meta-clonotypes from the SARS-CoV-2 antigen-associated TCRs that have strong evidence of restriction to patients with a specific human leukocyte antigen (HLA) genotype. Applied to independent cohorts, meta-clonotypes targeting these specific epitopes were more frequently detected in bulk repertoires compared to exact amino acid matches, and 59.7% (1093/1831) were more abundant among COVID-19 patients that expressed the putative restricting HLA allele (false discovery rate [FDR]<0.01), demonstrating the potential utility of meta-clonotypes as antigen-specific features for biomarker development. To enable further applications, we developed an open-source software package, tcrdist3, that implements this framework and facilitates flexible workflows for distance-based TCR repertoire analysis.


Subject(s)
Antigens, Viral/genetics , COVID-19/immunology , HLA Antigens/genetics , Receptors, Antigen, T-Cell/genetics , SARS-CoV-2/immunology , Antigens, Viral/immunology , Biomarkers , COVID-19/genetics , Complementarity Determining Regions/immunology , Computational Biology/methods , Epitopes/genetics , Epitopes/immunology , Genotype , HLA Antigens/immunology , Humans , Receptors, Antigen, T-Cell/immunology
6.
Cells ; 10(11)2021 11 15.
Article in English | MEDLINE | ID: covidwho-1523881

ABSTRACT

The production of specific neutralizing antibodies by individuals is thought to be the best option for reducing the number of patients with severe COVID-19, which is the reason why multiple vaccines are currently being administered worldwide. We aimed to explore the effect of revaccination with BCG, on the response to a subsequent anti-SARS-CoV-2 vaccine, in persons occupationally exposed to COVID-19 patients. Two groups of 30 randomized participants were selected: one group received a BCG revaccination, and the other group received a placebo. Subsequently, both groups were vaccinated against SARS-CoV-2. After each round of vaccination, the serum concentration of Th1/Th2 cytokines was determined. At the end of the protocol, neutralizing antibodies were determined and the HLA-DRB loci were genotyped. The participants from the BCG group and anti-SARS-CoV-2 vaccine group had increased serum cytokine concentrations (i.e., IL-1ß, IL-4, IL-6, IL-12p70, IL-13, IL-18, GM-CSF, INF-γ, and TNF-α) and higher neutralizing antibody titers, compared to the group with Placebo-anti-SARS-CoV-2. Twelve HLA-DRB1 alleles were identified in the Placebo-anti-SARS-CoV-2 group, and only nine in the group revaccinated with BCG. The DRB1*04 allele exhibited increased frequency in the Placebo-anti-SARS-CoV-2 group; however, no confounding effects were found with this allele. We conclude that revaccination with BCG synergizes with subsequent vaccination against SARS-CoV-2 in occupationally exposed personnel.


Subject(s)
BCG Vaccine/immunology , COVID-19/immunology , SARS-CoV-2/immunology , Adult , Antibodies, Neutralizing/blood , Antibodies, Viral/blood , BCG Vaccine/administration & dosage , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Cytokines/blood , Female , Genotype , HLA Antigens/genetics , Health Personnel , Humans , Immunization, Secondary , Male , Middle Aged , Occupational Exposure , Vaccination
7.
HLA ; 99(1): 25-30, 2022 01.
Article in English | MEDLINE | ID: covidwho-1522855

ABSTRACT

The ability of COVID-19 vaccination to induce anti-HLA antibodies (Abs) formation in renal transplant candidates is not well studied. A 42-year-old man on a renal transplant waitlist, with no sensitization history, was tested for DSA before and after COVID-19 vaccination. Patient has consistently tested negative for COVID-19 virus. Eighteen days after receiving first dose of mRNA-based vaccine, flow cytometry crossmatch (FCXM) was strongly positive with de novo donor-specific Ab (dnDSA) against B57 and de novo non-DSA against B58. Before vaccination, preliminary FCXM was negative with no anti-HLA Abs. This event prompted the transplant team to cancel the surgery. COVID-19 vaccination could be associated with anti-HLA Abs formation in renal patients on waitlists that could affect future transplantability.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19 , Isoantibodies/blood , Kidney Transplantation , Adult , Alleles , COVID-19/prevention & control , Graft Rejection/prevention & control , HLA Antigens/genetics , Humans , Male , Vaccination , Waiting Lists
8.
Pathol Res Pract ; 228: 153647, 2021 Dec.
Article in English | MEDLINE | ID: covidwho-1458650

ABSTRACT

Coronavirus disease 2019 (COVID-19) is a viral disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). COVID-19 is more serious in people with underlying diseases, but the cause of healthy people with progressive disease is largely unknown. Host genetic factors such as ACE2 variants, IFITM-3, HLA, TMRSS2, and furin polymorphisms appear to be one of the agents involved in the progression of the COVID-19 and outcome of the disease. This review discusses the general characteristics of SARS-CoV-2, including viral features, receptors, cell entry, clinical findings, and the main human genetic factors that may contribute to the pathogenesis of COVID-19 and get the patients' situation more complex. Further knowledge in this context may help to find a way to prevent and treat this viral pneumonia.


Subject(s)
COVID-19/virology , SARS-CoV-2/pathogenicity , Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Furin/genetics , Genetic Predisposition to Disease , HLA Antigens/genetics , Humans , Membrane Proteins/genetics , Polymorphism, Genetic , RNA-Binding Proteins/genetics
9.
Genes (Basel) ; 12(8)2021 08 19.
Article in English | MEDLINE | ID: covidwho-1456321

ABSTRACT

In dogs, symmetrical lupoid onychodystrophy (SLO) results in nail loss and an abnormal regrowth of the claws. In Bearded Collies, an autoimmune nature has been suggested because certain dog leukocyte antigen (DLA) class II haplotypes are associated with the condition. A genome-wide association study of the Bearded Collie revealed two regions of association that conferred risk for disease: one on canine chromosome (CFA) 12 that encompasses the DLA genes, and one on CFA17. Case-control association was employed on whole genome sequencing data to uncover putative causative variants in SLO within the CFA12 and CFA17 associated regions. Genotype imputation was then employed to refine variants of interest. Although no SLO-associated protein-coding variants were identified on CFA17, multiple variants, many with predicted damaging effects, were identified within potential candidate genes on CFA12. Furthermore, many potentially damaging alleles were fully correlated with the presence of DLA class II risk haplotypes for SLO, suggesting that the variants may reflect DLA class II haplotype association with disease or vice versa. Strong linkage disequilibrium in the region precluded the ability to isolate and assess the individual or combined effect of variants on disease development. Nonetheless, all were predictive of risk for SLO and, with judicious assessment, their application in selective breeding may prove useful to reduce the incidence of SLO in the breed.


Subject(s)
Dog Diseases/genetics , Genetic Predisposition to Disease , HLA Antigens/genetics , Alleles , Animals , Chromosomes/genetics , Dog Diseases/pathology , Dogs , Genome-Wide Association Study , Genotype , Haplotypes/genetics , Linkage Disequilibrium/genetics , Polymorphism, Single Nucleotide/genetics , Whole Genome Sequencing
10.
Virus Res ; 305: 198579, 2021 11.
Article in English | MEDLINE | ID: covidwho-1433887

ABSTRACT

The SARS-CoV2 mediated Covid-19 pandemic has impacted humankind at an unprecedented scale. While substantial research efforts have focused towards understanding the mechanisms of viral infection and developing vaccines/ therapeutics, factors affecting the susceptibility to SARS-CoV2 infection and manifestation of Covid-19 remain less explored. Given that the Human Leukocyte Antigen (HLA) system is known to vary among ethnic populations, it is likely to affect the recognition of the virus, and in turn, the susceptibility to Covid-19. To understand this, we used bioinformatic tools to probe all SARS-CoV2 peptides which could elicit T-cell response in humans. We also tried to answer the intriguing question of whether these potential epitopes were equally immunogenic across ethnicities, by studying the distribution of HLA alleles among different populations and their share of cognate epitopes. Results indicate that the immune recognition potential of SARS-CoV2 epitopes tend to vary between different ethnic groups. While the South Asians are likely to recognize higher number of CD8-specific epitopes, Europeans are likely to identify higher number of CD4-specific epitopes. We also hypothesize and provide clues that the newer mutations in SARS-CoV2 are unlikely to alter the T-cell mediated immunogenic responses among the studied ethnic populations. The work presented herein is expected to bolster our understanding of the pandemic, by providing insights into differential immunological response of ethnic populations to the virus as well as by gaging the possible effects of mutations in SARS-CoV2 on efficacy of potential epitope-based vaccines through evaluating ∼40,000 viral genomes.


Subject(s)
COVID-19/immunology , Epitopes, B-Lymphocyte/immunology , Epitopes, T-Lymphocyte/immunology , Genome, Viral , HLA Antigens/immunology , SARS-CoV-2/immunology , Africa/epidemiology , Alleles , Amino Acid Sequence , Asia/epidemiology , CD4-Positive T-Lymphocytes/immunology , CD4-Positive T-Lymphocytes/virology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , COVID-19/epidemiology , COVID-19/genetics , COVID-19/pathology , Computational Biology/methods , Disease Susceptibility , Epitopes, B-Lymphocyte/classification , Epitopes, B-Lymphocyte/genetics , Epitopes, T-Lymphocyte/classification , Epitopes, T-Lymphocyte/genetics , Europe/epidemiology , HLA Antigens/classification , HLA Antigens/genetics , Humans , Middle East/epidemiology , Oceania/epidemiology , Principal Component Analysis , RNA, Viral/genetics , RNA, Viral/immunology , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity
11.
Signal Transduct Target Ther ; 6(1): 344, 2021 09 20.
Article in English | MEDLINE | ID: covidwho-1428800

ABSTRACT

Coronavirus disease 2019 (COVID-19) caused by a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in considerable morbidity and mortality worldwide. COVID-19 incidence, severity, and mortality rates differ greatly between populations, genders, ABO blood groups, human leukocyte antigen (HLA) genotypes, ethnic groups, and geographic backgrounds. This highly heterogeneous SARS-CoV-2 infection is multifactorial. Host genetic factors such as variants in the angiotensin-converting enzyme gene (ACE), the angiotensin-converting enzyme 2 gene (ACE2), the transmembrane protease serine 2 gene (TMPRSS2), along with HLA genotype, and ABO blood group help to explain individual susceptibility, severity, and outcomes of COVID-19. This review is focused on COVID-19 clinical and viral characteristics, pathogenesis, and genetic findings, with particular attention on genetic diversity and variants. The human genetic basis could provide scientific bases for disease prediction and targeted therapy to address the COVID-19 scourge.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/genetics , Peptidyl-Dipeptidase A/genetics , SARS-CoV-2/genetics , ABO Blood-Group System/genetics , COVID-19/epidemiology , COVID-19/virology , Female , Genotype , HLA Antigens/genetics , Humans , Male , Risk Factors , SARS-CoV-2/pathogenicity , Serine Endopeptidases/genetics
12.
Immunogenetics ; 73(6): 449-458, 2021 12.
Article in English | MEDLINE | ID: covidwho-1427233

ABSTRACT

Associations between inherited Killer Immunoglobulin-like Receptor (KIR) genotypes and the severity of multiple RNA virus infections have been reported. This prospective study was initiated to investigate if such an association exists for COVID-19. In this cohort study performed at Ankara University, 132 COVID-19 patients (56 asymptomatic, 51 mild-intermediate, and 25 patients with severe disease) were genotyped for KIR and ligands. Ankara University Donor Registry (n:449) KIR data was used for comparison. Clinical parameters (age, gender, comorbidities, blood group antigens, inflammation biomarkers) and KIR genotypes across cohorts of asymptomatic, mild-intermediate, or severe disease were compared to construct a risk prediction model based on multivariate binary logistic regression analysis with backward elimination method. Age, blood group, number of comorbidities, CRP, D-dimer, and telomeric and centromeric KIR genotypes (tAA, tAB1, and cAB1) along with their cognate ligands were found to differ between cohorts. Two prediction models were constructed; both included age, number of comorbidities, and blood group. Inclusion of the KIR genotypes in the second prediction model exp (-3.52 + 1.56 age group - 2.74 blood group (type A vs others) + 1.26 number of comorbidities - 2.46 tAB1 with ligand + 3.17 tAA with ligand) increased the predictive performance with a 92.9% correct classification for asymptomatic and 76% for severe cases (AUC: 0.93; P < 0.0001, 95% CI 0.88, 0.99). This novel risk model, consisting of KIR genotypes with their cognate ligands, and clinical parameters but excluding earlier published inflammation-related biomarkers allow for the prediction of the severity of COVID-19 infection prior to the onset of infection. This study is listed in the National COVID-19 clinical research studies database.


Subject(s)
COVID-19/genetics , Genetic Predisposition to Disease/genetics , Receptors, KIR/genetics , Severity of Illness Index , Adult , Aged , Aged, 80 and over , COVID-19/diagnosis , COVID-19/epidemiology , Female , Genetic Predisposition to Disease/epidemiology , HLA Antigens/genetics , Haplotypes , Humans , Ligands , Male , Middle Aged , Models, Statistical , Prospective Studies , ROC Curve , Risk Assessment , SARS-CoV-2 , Turkey/epidemiology
13.
Front Immunol ; 12: 728936, 2021.
Article in English | MEDLINE | ID: covidwho-1413272

ABSTRACT

The use of minimal peptide sets offers an appealing alternative for design of vaccines and T cell diagnostics compared to conventional whole protein approaches. T cell immunogenicity towards peptides is contingent on binding to human leukocyte antigen (HLA) molecules of the given individual. HLA is highly polymorphic, and each variant typically presents a different repertoire of peptides. This polymorphism combined with pathogen diversity challenges the rational selection of peptide sets with broad immunogenic potential and population coverage. Here we propose PopCover-2.0, a simple yet highly effective method, for resolving this challenge. The method takes as input a set of (predicted) CD8 and/or CD4 T cell epitopes with associated HLA restriction and pathogen strain annotation together with information on HLA allele frequencies, and identifies peptide sets with optimal pathogen and HLA (class I and II) coverage. PopCover-2.0 was benchmarked on historic data in the context of HIV and SARS-CoV-2. Further, the immunogenicity of the selected SARS-CoV-2 peptides was confirmed by experimentally validating the peptide pools for T cell responses in a panel of SARS-CoV-2 infected individuals. In summary, PopCover-2.0 is an effective method for rational selection of peptide subsets with broad HLA and pathogen coverage. The tool is available at https://services.healthtech.dtu.dk/service.php?PopCover-2.0.


Subject(s)
Epitopes, T-Lymphocyte/immunology , HLA Antigens/genetics , HLA Antigens/immunology , Peptides/immunology , Alleles , Allergy and Immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , COVID-19/immunology , COVID-19/prevention & control , Genotype , HLA Antigens/classification , Humans , Immunogenicity, Vaccine , Immunologic Techniques , Peptides/classification , SARS-CoV-2/immunology
14.
Eur J Med Res ; 26(1): 107, 2021 Sep 16.
Article in English | MEDLINE | ID: covidwho-1412355

ABSTRACT

BACKGROUND: COVID-19, the pandemic disease caused by infection with SARS-CoV-2, may take highly variable clinical courses, ranging from symptom-free and pauci-symptomatic to fatal disease. The goal of the current study was to assess the association of COVID-19 clinical courses controlled by patients' adaptive immune responses without progression to severe disease with patients' Human Leukocyte Antigen (HLA) genetics, AB0 blood group antigens, and the presence or absence of near-loss-of-function delta 32 deletion mutant of the C-C chemokine receptor type 5 (CCR5). PATIENT AND METHODS: An exploratory observational study including 157 adult COVID-19 convalescent patients was performed with a median follow-up of 250 days. The impact of different HLA genotypes, AB0 blood group antigens, and the CCR5 mutant CD195 were investigated for their role in the clinical course of COVID-19. In addition, this study addressed levels of severity and morbidity of COVID-19. The association of the immunogenetic background parameters were further related to patients' humoral antiviral immune response patterns by longitudinal observation. RESULTS: Univariate HLA analyses identified putatively protective HLA alleles (HLA class II DRB1*01:01 and HLA class I B*35:01, with a trend for DRB1*03:01). They were associated with reduced durations of disease instead decreased (rather than increased) total anti-S IgG levels. They had a higher virus neutralizing capacity compared to non-carriers. Conversely, analyses also identified HLA alleles (HLA class II DQB1*03:02 und HLA class I B*15:01) not associated with such benefit in the patient cohort of this study. Hierarchical testing by Cox regression analyses confirmed the significance of the protective effect of the HLA alleles identified (when assessed in composite) in terms of disease duration, whereas AB0 blood group antigen heterozygosity was found to be significantly associated with disease severity (rather than duration) in our cohort. A suggestive association of a heterozygous CCR5 delta 32 mutation status with prolonged disease duration was implied by univariate analyses but could not be confirmed by hierarchical multivariate testing. CONCLUSION: The current study shows that the presence of HLA class II DRB1*01:01 and HLA class I B*35:01 is of even stronger association with reduced disease duration in mild and moderate COVID-19 than age or any other potential risk factor assessed. Prospective studies in larger patient populations also including novel SARS-CoV-2 variants will be required to assess the impact of HLA genetics on the capacity of mounting protective vaccination responses in the future.


Subject(s)
ABO Blood-Group System/genetics , COVID-19/etiology , HLA Antigens/genetics , Receptors, CCR5/genetics , Adult , Aged , COVID-19/epidemiology , COVID-19/genetics , Female , Genetic Predisposition to Disease , Genotype , HLA-DRB1 Chains/genetics , Histocompatibility Antigens Class I/genetics , Humans , Immunoglobulin G/blood , Male , Middle Aged , Morbidity , Mutation , Severity of Illness Index
15.
HLA ; 96(3): 277-298, 2020 09.
Article in English | MEDLINE | ID: covidwho-1388402

ABSTRACT

We report detailed peptide-binding affinities between 438 HLA Class I and Class II proteins and complete proteomes of seven pandemic human viruses, including coronaviruses, influenza viruses and HIV-1. We contrast these affinities with HLA allele frequencies across hundreds of human populations worldwide. Statistical modelling shows that peptide-binding affinities classified into four distinct categories depend on the HLA locus but that the type of virus is only a weak predictor, except in the case of HIV-1. Among the strong HLA binders (IC50 ≤ 50), we uncovered 16 alleles (the top ones being A*02:02, B*15:03 and DRB1*01:02) binding more than 1% of peptides derived from all viruses, 9 (top ones including HLA-A*68:01, B*15:25, C*03:02 and DRB1*07:01) binding all viruses except HIV-1, and 15 (top ones A*02:01 and C*14:02) only binding coronaviruses. The frequencies of strongest and weakest HLA peptide binders differ significantly among populations from different geographic regions. In particular, Indigenous peoples of America show both higher frequencies of strongest and lower frequencies of weakest HLA binders. As many HLA proteins are found to be strong binders of peptides derived from distinct viral families, and are hence promiscuous (or generalist), we discuss this result in relation to possible signatures of natural selection on HLA promiscuous alleles due to past pathogenic infections. Our findings are highly relevant for both evolutionary genetics and the development of vaccine therapies. However they should not lead to forget that individual resistance and vulnerability to diseases go beyond the sole HLA allelic affinity and depend on multiple, complex and often unknown biological, environmental and other variables.


Subject(s)
Coronavirus Infections/epidemiology , HIV Infections/epidemiology , HLA Antigens/chemistry , Influenza, Human/epidemiology , Pandemics , Peptides/chemistry , Pneumonia, Viral/epidemiology , Severe Acute Respiratory Syndrome/epidemiology , Viral Proteins/chemistry , Africa/epidemiology , Americas/epidemiology , Amino Acid Sequence , Asia/epidemiology , Australia/epidemiology , Betacoronavirus/genetics , Betacoronavirus/immunology , COVID-19 , Computational Biology , Coronavirus Infections/immunology , Coronavirus Infections/virology , Europe/epidemiology , HIV Infections/immunology , HIV Infections/virology , HIV-1/genetics , HIV-1/immunology , HLA Antigens/classification , HLA Antigens/genetics , HLA Antigens/immunology , Humans , Influenza A Virus, H1N1 Subtype/genetics , Influenza A Virus, H1N1 Subtype/immunology , Influenza A Virus, H3N2 Subtype/genetics , Influenza A Virus, H3N2 Subtype/immunology , Influenza A Virus, H7N9 Subtype/genetics , Influenza A Virus, H7N9 Subtype/immunology , Influenza, Human/immunology , Influenza, Human/virology , Kinetics , Middle East Respiratory Syndrome Coronavirus/genetics , Middle East Respiratory Syndrome Coronavirus/immunology , Peptides/genetics , Peptides/immunology , Pneumonia, Viral/immunology , Pneumonia, Viral/virology , Protein Binding , SARS Virus/genetics , SARS Virus/immunology , SARS-CoV-2 , Severe Acute Respiratory Syndrome/immunology , Severe Acute Respiratory Syndrome/virology , Viral Proteins/genetics , Viral Proteins/immunology
16.
HLA ; 98(3): 265-312, 2021 09.
Article in English | MEDLINE | ID: covidwho-1379603
17.
Nucleic Acids Res ; 50(D1): D883-D887, 2022 01 07.
Article in English | MEDLINE | ID: covidwho-1358469

ABSTRACT

Rapidly appearing SARS-CoV-2 mutations can affect T cell epitopes, which can help the virus to evade either CD8 or CD4 T-cell responses. We developed T-cell COVID-19 Atlas (T-CoV, https://t-cov.hse.ru) - the comprehensive web portal, which allows one to analyze how SARS-CoV-2 mutations alter the presentation of viral peptides by HLA molecules. The data are presented for common virus variants and the most frequent HLA class I and class II alleles. Binding affinities of HLA molecules and viral peptides were assessed with accurate in silico methods. The obtained results highlight the importance of taking HLA alleles diversity into account: mutation-mediated alterations in HLA-peptide interactions were highly dependent on HLA alleles. For example, we found that the essential number of peptides tightly bound to HLA-B*07:02 in the reference Wuhan variant ceased to be tight binders for the Indian (Delta) and the UK (Alpha) variants. In summary, we believe that T-CoV will help researchers and clinicians to predict the susceptibility of individuals with different HLA genotypes to infection with variants of SARS-CoV-2 and/or forecast its severity.


Subject(s)
COVID-19/immunology , Databases, Factual , HLA Antigens/metabolism , SARS-CoV-2/genetics , Alleles , COVID-19/virology , Codon, Terminator , Epitopes, T-Lymphocyte/immunology , HLA Antigens/genetics , HLA Antigens/immunology , HLA-B7 Antigen/immunology , Host-Pathogen Interactions , Humans , India , Mutation , SARS-CoV-2/pathogenicity , United Kingdom , Viral Proteins/genetics , Viral Proteins/immunology
18.
Eur J Med Res ; 26(1): 84, 2021 Aug 03.
Article in English | MEDLINE | ID: covidwho-1339152

ABSTRACT

The COVID-19 pandemic has markedly impacted on cultural, political, and economic structures all over the world. Several aspects of its pathogenesis and related clinical consequences have not yet been elucidated. Infection rates, as well morbidity and mortality differed within countries. It is intriguing for scientists to understand how patient genetics may influence the outcome of the condition, to clarify which aspects could be related the clinical variability of SARS-CoV-2 disease. We reviewed the studies exploring the role of human leukocyte antigens (HLA) genotypes on individual responses to SARS-CoV-2 infection and/or progression, discussing also the contribution of the immunological patterns MHC-related. In March 2021, the main online databases were accessed. All the articles that investigated the possible association between the HLA genotypes and related polymorphisms with susceptibility, severity and progression of COVID-19 were considered. Although both genetic and environmental factors are certainly expected to influence the susceptibility to or protection of individuals, the HLA and related polymorphisms can influence susceptibility, progression and severity of SARS-CoV-2 infection. The crucial role played by HLA molecules in the immune response, especially through pathogen-derived peptide presentation, and the huge molecular variability of HLA alleles in the human populations could be responsible for the different rates of infection and the different patients following COVID-19 infection.


Subject(s)
COVID-19/genetics , Genetic Predisposition to Disease , HLA Antigens/genetics , SARS-CoV-2 , Alleles , COVID-19/etiology , COVID-19/immunology , Disease Progression , Genotype , Humans , Severity of Illness Index
19.
Hum Immunol ; 82(10): 713-718, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1322117

ABSTRACT

A disproportionate incidence of death has occurred in African Americans (Blacks) in the United States due to COVID-19. The reason for this disparity is likely to be multi-factorial and may involve genetic predisposition. The association of human leukocyte antigens (HLA) with severe COVID-19 was examined in a hospitalized population (89% Black, n = 36) and compared to HLA typed non-hospitalized individuals (20% Black, n = 40) who had recovered from mild disease. For additional comparison, HLA typing data was available from kidney transplant recipients and deceased donors. Hospitalized patients were followed for 45 days after admission to our medical center with death as the primary end-point. One HLA allele, B53, appeared to be more prevalent in the hospitalized COVID-19 patients (percent of positive subjects, 30.5) compared to national data in US Black populations (percent of positive subjects, 24.5). The percent B53 positive in non-hospitalized COVID-19 patients was 2.6, significantly less than the percent positive in the hospitalized COVID-19 patients (p = 0.001, Fisher's exact test) and less than the 8 percent positive listed in national data bases for US Caucasian populations. Significantly greater deaths (73 percent) were observed in HLA B53 positive hospitalized COVID-19 patients compared to hospitalized COVID-19 patients who were B53 negative (40 percent). Multi-variate analysis indicated that HLA B53 positive Black hospitalized COVID-19 patients were at a 7.4 fold greater risk of death than Black COVID-19 patients who were B53 negative. Consideration for accelerated vaccination and treatment should be given to HLA B53 positive Black COVID19 patients.


Subject(s)
COVID-19/genetics , Genetic Predisposition to Disease/genetics , HLA Antigens/genetics , African Americans/genetics , Female , Hospitalization , Humans , Male , SARS-CoV-2/pathogenicity , United States
20.
J Clin Pathol ; 74(8): 528-532, 2021 Aug.
Article in English | MEDLINE | ID: covidwho-1318062

ABSTRACT

AIMS: Brazil is nowadays one of the epicentres of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic and new therapies are needed to face it. In the context of specific immune response against the virus, a correlation between Major Histocompatibility Complex Class I (MHC-I) and the severity of the disease in patients with COVID-19 has been suggested. Aiming at better understanding the biology of the infection and the immune response against the virus in the Brazilian population, we analysed SARS-CoV-2 protein S peptides in order to identify epitopes able to elicit an immune response mediated by the most frequent MHC-I alleles using in silico methods. METHODS: Our analyses consisted in searching for the most frequent Human Leukocyte Antigen (HLA)-A, HLA-B and HLA-C alleles in the Brazilian population, excluding the genetic isolates; then, we performed: molecular modelling for unsolved structures, MHC-I binding affinity and antigenicity prediction, peptide docking and molecular dynamics of the best fitted MHC-I/protein S complexes. RESULTS: We identified 24 immunogenic epitopes in the SARS-CoV-2 protein S that could interact with 17 different MHC-I alleles (namely, HLA-A*01:01; HLA-A*02:01; HLA-A*11:01; HLA-A*24:02; HLA-A*68:01; HLA-A*23:01; HLA-A*26:01; HLA-A*30:02; HLA-A*31:01; HLA-B*07:02; HLA-B*51:01; HLA-B*35:01; HLA-B*44:02; HLA-B*35:03; HLA-C*05:01; HLA-C*07:01 and HLA-C*15:02) in the Brazilian population. CONCLUSIONS: Being aware of the intrinsic limitations of in silico analysis (mainly the differences between the real and the Protein Data Bank (PDB) structure; and accuracy of the methods for simulate proteasome cleavage), we identified 24 epitopes able to interact with 17 MHC-I more frequent alleles in the Brazilian population that could be useful for the development of strategic methods for vaccines against SARS-CoV-2.


Subject(s)
Epitope Mapping , Epitopes , HLA Antigens/immunology , Histocompatibility Antigens Class I/immunology , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/immunology , Brazil , Gene Frequency , HLA Antigens/genetics , Histocompatibility Antigens Class I/genetics , Host-Pathogen Interactions , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Protein Binding , Protein Conformation , SARS-CoV-2/pathogenicity
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