{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T06:25:02Z","timestamp":1787034302262,"version":"build-2736575974"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T00:00:00Z","timestamp":1787011200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>The human leukocyte antigen (HLA) system plays a critical role in determining the outcomes of hepatitis B virus (HBV) infection, yet the genetic mechanisms underlying occult HBV infection (OBI), a form marked by detectable HBV DNA in the absence of hepatitis B surface antigen, remain poorly defined. Here, we performed high-resolution HLA genotyping and amino acid-based association analysis in a Chinese population comprising 239 OBI cases and 545 healthy controls. We identified the HLA class II allele DQB1*06:02 as a protective signal against OBI, with conditional analysis confirming its independent effect. This allele is carried on the conserved haplotype DRB1*15:01~DQA1*02:01~DQB1*06:02, which was significantly underrepresented in OBI cases. Conversely, the DRB1*09:01~DQA1*03:02~DQB1*03:03 haplotype was associated with increased OBI risk. Analysis of the HLA-DQB1 amino acid residues revealed that position 119, located in an \u03b1-helix of the peptide-binding groove, drives a substantial portion of the observed association. The phenylalanine variant at this site remained strongly protective after multiple-testing correction and is encoded by DQB1*06:02. Our study thus delineates both allele and amino acid level HLA determinants of OBI susceptibility, highlighting a key structural residue that may influence antigen presentation and immune clearance of HBV. These findings provide a refined genetic framework for understanding host and virus interactions in occult HBV persistence.<\/jats:p>","DOI":"10.3389\/fimmu.2026.1898993","type":"journal-article","created":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:35:59Z","timestamp":1787031359000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["HLA-DQB1*06:02 and a critical amino acid variant in protection against occult hepatitis B virus infection"],"prefix":"10.3389","volume":"17","author":[{"given":"Mimi","family":"Wu","sequence":"first","affiliation":[{"name":"Blood Center of Zhejiang Province, Institute of Transfusion Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenwen","family":"Pi","sequence":"additional","affiliation":[{"name":"Blood Center of Zhejiang Province, Institute of Transfusion Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Li","sequence":"additional","affiliation":[{"name":"Blood Center of Zhejiang Province, Institute of Transfusion Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhen","family":"He","sequence":"additional","affiliation":[{"name":"Blood Center of Zhejiang Province, Institute of Transfusion Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangshu","family":"Yu","sequence":"additional","affiliation":[{"name":"Medical Test Laboratory, Blood Center of Zhejiang Province","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong","family":"Zhu","sequence":"additional","affiliation":[{"name":"Medical Test Laboratory, Blood Center of Zhejiang Province","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhipan","family":"Wu","sequence":"additional","affiliation":[{"name":"Blood Center of Zhejiang Province, Institute of Transfusion Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji","family":"He","sequence":"additional","affiliation":[{"name":"Blood Center of Zhejiang Province, Institute of Transfusion Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanmin","family":"He","sequence":"additional","affiliation":[{"name":"Blood Center of Zhejiang Province, Institute of Transfusion Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Faming","family":"Zhu","sequence":"additional","affiliation":[{"name":"Blood Center of Zhejiang Province, Institute of Transfusion Medicine","place":["Hangzhou, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-023-00760-9","article-title":"Global burden of hepatitis B virus: current status, missed opportunities and a call for action","volume":"20","author":"Hsu","year":"2023","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"397","DOI":"10.1016\/j.jhep.2019.03.034","article-title":"Update of the statements on biology and clinical impact of occult hepatitis B virus infection","volume":"71","author":"Raimondo","year":"2019","journal-title":"J Hepatol"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2020.05.042","article-title":"Occult hepatitis B infection and hepatocellular carcinoma: epidemiology, virology, hepatocarcinogenesis and clinical significance","volume":"73","author":"Mak","year":"2020","journal-title":"J Hepatol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2025.1663306","article-title":"Transfusion-transmitted occult hepatitis B virus infection: current understanding, challenges, and its implication in blood safety","volume":"16","author":"Huang","year":"2025","journal-title":"Front Immunol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1128\/JCM.00145-11","article-title":"Characterization of occult hepatitis B virus infection from blood donors in China","volume":"49","author":"Zheng","year":"2011","journal-title":"J Clin Microbiol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v30.i26.3193","article-title":"Reactivation of hepatitis B virus infection - an important aspect of multifaceted problem","volume":"30","author":"Morozov","year":"2024","journal-title":"World J Gastroenterol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-316490","article-title":"Multiple HBV transfusion transmissions from undetected occult infections: revising the minimal infectious dose","volume":"68","author":"Candotti","year":"2019","journal-title":"Gut"},{"key":"B8","doi-asserted-by":"publisher","first-page":"87","DOI":"10.55133\/eji.310110","article-title":"Insight on the hepatitis B virus and host immune mechanisms in the context of occult hepatitis","volume":"31","author":"El Said","year":"2024","journal-title":"Egypt J Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s00251-017-0986-6","article-title":"Introduction: MHC\/KIR and governance of specificity","volume":"69","author":"Kelly","year":"2017","journal-title":"Immunogenetics"},{"key":"B10","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1016\/j.it.2023.07.005","article-title":"Factors contributing to the potency of CD8(+) T cells","volume":"44","author":"Sykulev","year":"2023","journal-title":"Trends Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1146\/annurev.iy.12.040194.001355","article-title":"Assembly, transport, and function of MHC class II molecules","volume":"12","author":"Cresswell","year":"1994","journal-title":"Annu Rev Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v19.i33.5395","article-title":"HLA class II associated with outcomes of hepatitis B and C infections","volume":"19","author":"Tamori","year":"2013","journal-title":"World J Gastroenterol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000001307","article-title":"HLA-DQB1*03:01 and risk of HBV-related HCC","volume":"83","author":"Zhang","year":"2026","journal-title":"Hepatology"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1186\/s12865-022-00496-2","article-title":"High resolution HLA-DRB1 analysis and shared molecular amino acid signature of DRbeta1 molecules in Occult hepatitis B infection","volume":"23","author":"Wang","year":"2022","journal-title":"BMC Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1002\/mgg3.2102","article-title":"Haplotype-dependent HLA-DRB1-DQB1 susceptibility to occult HBV infection in Xi'an Han population","volume":"11","author":"Wang","year":"2023","journal-title":"Mol Genet Genomic Med"},{"key":"B16","doi-asserted-by":"publisher","first-page":"5902","DOI":"10.1038\/ncomms6902","article-title":"The HLA-DRbeta1 amino acid positions 11-13-26 explain the majority of SLE-MHC associations","volume":"5","author":"Kim","year":"2014","journal-title":"Nat Commun"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1681\/ASN.2016020114","article-title":"MHC class II risk alleles and amino acid residues in idiopathic membranous nephropathy","volume":"28","author":"Cui","year":"2017","journal-title":"J Am Soc Nephrol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s00251-024-01349-5","article-title":"The characteristic of HLA-A, HLA-B, HLA-C, HLA-DRB1, HLA-DRB3\/4\/5, HLA-DQA1, HLA-DQB1, HLA-DPA1, and HLA-DPB1 alleles in Zhejiang Han population","volume":"76","author":"Tao","year":"2024","journal-title":"Immunogenetics"},{"key":"B19","doi-asserted-by":"publisher","first-page":"714","DOI":"10.1186\/s12879-021-06468-y","article-title":"Characteristic of HBV nucleic acid amplification testing yields from blood donors in China","volume":"21","author":"Wu","year":"2021","journal-title":"BMC Infect Dis"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.710414","article-title":"Association of HLA-DPA1, HLA-DPB1, and HLA-DQB1 alleles with the long-term and booster immune responses of young adults vaccinated against the hepatitis B virus as neonates","volume":"12","author":"Wang","year":"2021","journal-title":"Front Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1111\/apt.15887","article-title":"Large-scale genome-wide association study identifies HLA class II variants associated with chronic HBV infection: a study from Taiwan Biobank","volume":"52","author":"Huang","year":"2020","journal-title":"Aliment Pharmacol Ther"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.3748\/wjg.v20.i25.8179","article-title":"Association of human leukocyte antigen DQB1 and DRB1 alleles with chronic hepatitis B","volume":"20","author":"Doganay","year":"2014","journal-title":"World J Gastroenterol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1186\/s12967-018-1716-z","article-title":"The roles of HLA-DQB1 gene polymorphisms in hepatitis B virus infection","volume":"16","author":"Ou","year":"2018","journal-title":"J Transl Med"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2013.06.108","article-title":"The effect of HLA on immunological response to hepatitis B vaccine in healthy people: a meta-analysis","volume":"31","author":"Li","year":"2013","journal-title":"Vaccine"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.2337\/db23-0387","article-title":"Increased frequency of the HLA-DRB1*04:04-DQA1*03-DQB1*03:02 haplotype among HLA-DQB1*06:02-positive children with type 1 diabetes","volume":"73","author":"Ilonen","year":"2024","journal-title":"Diabetes"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1212\/WNL.0b013e3181f9630d","article-title":"Why do we respond differently to sleep deprivation?: it's in our genes","volume":"75","author":"Verma","year":"2010","journal-title":"Neurology"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2012.01.004","article-title":"DQB1*06:02 allele-specific expression varies by allelic dosage, not narcolepsy status","volume":"73","author":"Weiner Lachmi","year":"2012","journal-title":"Hum Immunol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"458","DOI":"10.3390\/cimb47060458","article-title":"HLA-DRB1 and DQB1 allelic polymorphism and multiple sclerosis in a moroccan population","volume":"47","author":"Fguirouche","year":"2025","journal-title":"Curr Issues Mol Biol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3390\/cimb46020067","article-title":"Molecular analysis of HLA genes in Romanian patients with chronic hepatitis B virus infection","volume":"46","author":"Talangescu","year":"2024","journal-title":"Curr Issues Mol Biol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.sleep.2021.07.024","article-title":"Narcolepsy type 1 patients have lower levels of effector memory CD4(+) T cells compared to their siblings when controlling for H1N1-(Pandemrix)-vaccination and HLA DQB1 *06:02 status","volume":"85","author":"Viste","year":"2021","journal-title":"Sleep Med"},{"key":"B31","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/j.jneuroim.2017.05.001","article-title":"Absence of autoreactive CD4(+) T-cells targeting HLA-DQA1*01:02\/DQB1*06:02 restricted hypocretin\/orexin epitopes in narcolepsy type 1 when detected by EliSpot","volume":"309","author":"Kornum","year":"2017","journal-title":"J Neuroimmunol"},{"key":"B32","doi-asserted-by":"publisher","first-page":"898","DOI":"10.1038\/ng.3353","article-title":"Additive and interaction effects at three amino acid positions in HLA-DQ and HLA-DR molecules drive type 1 diabetes risk","volume":"47","author":"Hu","year":"2015","journal-title":"Nat Genet"},{"key":"B33","doi-asserted-by":"publisher","first-page":"1639","DOI":"10.1038\/s41467-021-21975-x","article-title":"A deep learning method for HLA imputation and trans-ethnic MHC fine-mapping of type 1 diabetes","volume":"12","author":"Naito","year":"2021","journal-title":"Nat Commun"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1002\/jgm.2987","article-title":"Association of human leukocyte antigen polymorphisms with occult hepatitis B virus infection in a Shaanxi Han population","volume":"19","author":"Wang","year":"2017","journal-title":"J Gene Med"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1007\/s00439-025-02805-2","article-title":"Exploratory analysis of HLA SNPs associated with occult HBV infection: a multicenter case-control study in Chinese blood donors","volume":"145","author":"Zhou","year":"2025","journal-title":"Hum Genet"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.5501\/wjv.v11.i5.275","article-title":"Hepatitis B virus infection reactivation in patients under immunosuppressive therapies: Pathogenesis, screening, prevention and treatment","volume":"11","author":"Spera","year":"2022","journal-title":"World J Virol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1159\/000360943","article-title":"Therapy of occult hepatitis B virus infection and prevention of reactivation","volume":"57","author":"Raimondo","year":"2014","journal-title":"Intervirology"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.vaccine.2025.127130","article-title":"Characteristics of hepatitis B virus surface protein and occult hepatitis B infection in infants with immunoprophylaxis failure from Indonesia","volume":"56","author":"Wibowo","year":"2025","journal-title":"Vaccine"},{"key":"B39","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1038\/s41598-023-50907-6","article-title":"Prevalence and influential factors of isolated hepatitis B core antibody positivity in a Chinese adult population","volume":"14","author":"Wang","year":"2024","journal-title":"Sci Rep"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1898993\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:36:00Z","timestamp":1787031360000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1898993\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,18]]},"references-count":39,"alternative-id":["10.3389\/fimmu.2026.1898993"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1898993","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,18]]},"article-number":"1898993"}}