{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T10:48:01Z","timestamp":1785408481792,"version":"3.56.0"},"posted":{"date-parts":[[2026,6,6]]},"group-title":"Immunology","reference-count":31,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T00:00:00Z","timestamp":1780704000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"funder":[{"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/01q3tbs38","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/00c489v88","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/04e3zg361","id-type":"ROR","asserted-by":"publisher"}]},{"id":[{"id":"https:\/\/ror.org\/05q2q3076","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,5]]},"abstract":"ABSTRACT<\/jats:title>\n \n Background & Aims<\/jats:title>\n \n People with HBV\/HIV co-infection on antiretroviral therapy achieve higher rates of HBV functional cure than those with HBV mono-infection, yet the immunological basis remains poorly characterised. HBV-specific CD4\n +<\/jats:sup>\n T cell responses are critical for viral control and functional cure but have been scarcely examined in HBV\/HIV co-infection. Our previous studies in HBV\/HIV co-infection demonstrated preserved stem-like CD8\n +<\/jats:sup>\n T cells and NK cell functional responses, but whether CD4\n +<\/jats:sup>\n T cell helper function is similarly maintained is unknown.\n <\/jats:p>\n <\/jats:sec>\n \n Methods<\/jats:title>\n \n We analysed CD4\n +<\/jats:sup>\n T cell responses in 72 participants (HBV n=26, HBV\/HIV n=24, HIV n=22) on suppressive antiviral therapy, using multiparameter flow cytometry, virus-specific CD4\n +<\/jats:sup>\n T cell functional assays and proliferation assays.\n <\/jats:p>\n <\/jats:sec>\n \n Results<\/jats:title>\n \n People with HBV\/HIV co-infection had significantly higher HBV envelope- and core-specific CD4\n +<\/jats:sup>\n T cell responses, with IL-2 production particularly discriminating between groups. CD4\n +<\/jats:sup>\n T cell responses to CEF (CMV, EBV, and Influenza) were comparable, confirming antigen specificity. Granzyme B-expressing cytotoxic CD4\n +<\/jats:sup>\n T cells and TCF-1\n +<\/jats:sup>\n CD127\n +<\/jats:sup>\n PD-1\n +<\/jats:sup>\n CD4\n +<\/jats:sup>\n T cells were enriched in co-infection. CD4\n +<\/jats:sup>\n and CD8\n +<\/jats:sup>\n T cell responses were more frequently coordinated within donors in co-infection than in mono-infection (envelope 83% vs 50%; core 94% vs 60%), where they were more often uncoupled. IL-2 producing CD4\n +<\/jats:sup>\n T cells correlated with CD8\n +<\/jats:sup>\n T cell responses and the CD4:CD8 ratio in co-infection. HBV-specific proliferative capacity was enhanced in co-infection.\n <\/jats:p>\n <\/jats:sec>\n \n Conclusions<\/jats:title>\n \n People with HBV\/HIV co-infection mount functional HBV-specific CD4\n +<\/jats:sup>\n T helper responses that are coordinated with CD8\n +<\/jats:sup>\n T cell immunity at the individual level. Together with our prior findings of preserved NK and CD8\n +<\/jats:sup>\n T cell responses in this cohort, these data identify treated HBV\/HIV co-infection as a setting of integrated, rather than compromised, antiviral immunity.\n <\/jats:p>\n <\/jats:sec>\n \n Impact and Implications<\/jats:title>\n People with HBV\/HIV co-infection can achieve HBV functional cure more frequently than people with HBV mono-infection, but the immune mechanisms remain unclear. This study shows that treated HBV\/HIV co-infection is characterised by functional HBV-specific CD4\u207a helper responses and coordinated CD4\u207a\/CD8\u207a antiviral immunity. These responses were most strongly associated with the CD4:CD8 ratio, a routinely available clinical marker, rather than with CD4 count alone. These findings argue that people with HBV\/HIV co-infection should be prioritised in, not excluded from, HBV cure immunotherapy trials.<\/jats:p>\n <\/jats:sec>\n \n Graphical Abstract<\/jats:title>\n \n \n <\/jats:fig>\n <\/jats:sec>","DOI":"10.64898\/2026.06.04.730166","type":"posted-content","created":{"date-parts":[[2026,6,6]],"date-time":"2026-06-06T10:40:51Z","timestamp":1780742451000},"source":"Crossref","is-referenced-by-count":0,"title":["Preserved CD4\n +<\/sup>\n T cell helper function and coordinated antiviral immunity in people with HBV\/HIV co-infection on long-term therapy"],"prefix":"10.64898","author":[{"given":"Aljawharah","family":"Alrubayyi","sequence":"first","affiliation":[{"name":"Institute of Infection Immunity and Transplantation, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anucha","family":"Preechanukul","sequence":"additional","affiliation":[{"name":"Institute of Infection Immunity and Transplantation, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yinru","family":"Zhang","sequence":"additional","affiliation":[{"name":"Institute of Infection Immunity and Transplantation, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonida","family":"Kokici","sequence":"additional","affiliation":[{"name":"Institute of Infection Immunity and Transplantation, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tanu","family":"Kamat","sequence":"additional","affiliation":[{"name":"Institute of Infection Immunity and Transplantation, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Davies","sequence":"additional","affiliation":[{"name":"Institute of Infection Immunity and Transplantation, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Indrajit","family":"Ghosh","sequence":"additional","affiliation":[{"name":"Mortimer Market Clinic, Central Northwest London NHS Foundation Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fiona","family":"Burns","sequence":"additional","affiliation":[{"name":"Department of HIV Medicine, Royal Free London NHS Foundation Trust, London, UK"},{"name":"Institute for Global Health, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sabine","family":"Kinloch","sequence":"additional","affiliation":[{"name":"Department of HIV Medicine, Royal Free London NHS Foundation Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pedro","family":"Simoes","sequence":"additional","affiliation":[{"name":"Department of HIV Medicine, Royal Free London NHS Foundation Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sanjay","family":"Bhagani","sequence":"additional","affiliation":[{"name":"Department of HIV Medicine, Royal Free London NHS Foundation Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick T F","family":"Kennedy","sequence":"additional","affiliation":[{"name":"Barts Liver Centre, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mala K","family":"Maini","sequence":"additional","affiliation":[{"name":"Institute of Infection Immunity and Transplantation, University College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Upkar S","family":"Gill","sequence":"additional","affiliation":[{"name":"Barts Liver Centre, Barts & The London School of Medicine & Dentistry, Queen Mary University of London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dimitra","family":"Peppa","sequence":"additional","affiliation":[{"name":"Institute of Infection Immunity and Transplantation, University College London, London, UK"},{"name":"Mortimer Market Clinic, Central Northwest London NHS Foundation Trust, London, UK"},{"name":"Department of HIV Medicine, Royal Free London NHS Foundation Trust, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026060906150470000_2026.06.04.730166v1.1","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.13217"},{"key":"2026060906150470000_2026.06.04.730166v1.2","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000001574"},{"key":"2026060906150470000_2026.06.04.730166v1.3","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiz450"},{"key":"2026060906150470000_2026.06.04.730166v1.4","doi-asserted-by":"publisher","DOI":"10.1097\/QAI.0000000000002386"},{"key":"2026060906150470000_2026.06.04.730166v1.5","doi-asserted-by":"crossref","unstructured":"Zheng, J.-R. , Wang, Z.-L. & Feng, B . Hepatitis B functional cure and immune response. Front. Immunol. 13, 1075916 (2022).","DOI":"10.3389\/fimmu.2022.1075916"},{"key":"2026060906150470000_2026.06.04.730166v1.6","doi-asserted-by":"crossref","first-page":"1341","DOI":"10.3390\/v13071341","article-title":"Functional Cure of Hepatitis B Virus Infection in Individuals With HIV-Coinfection: A Literature Review","volume":"13","year":"2021","journal-title":"Viruses"},{"key":"2026060906150470000_2026.06.04.730166v1.7","doi-asserted-by":"crossref","unstructured":"Feuerherd M , Mischke J , & Lauer GM . T-cell profiles in HBV functional cure and people living with HIV: known knowns, known unknowns, and unknown unknowns. Curr. HIV\/AIDS Rep. 23, 9 (2026).","DOI":"10.1007\/s11904-026-00777-0"},{"key":"2026060906150470000_2026.06.04.730166v1.8","doi-asserted-by":"crossref","first-page":"140","DOI":"10.1097\/COH.0000000000001002","article-title":"Hepatitis B virus functional cure in persons with HIV: what are the predictors and which novel markers are useful?","volume":"21","year":"2026","journal-title":"Curr. Opin. HIV AIDS"},{"key":"2026060906150470000_2026.06.04.730166v1.9","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.77.1.68-76.2003"},{"key":"2026060906150470000_2026.06.04.730166v1.10","doi-asserted-by":"crossref","unstructured":"Jespersen, J. M. et al. Clinical cure of chronic hepatitis B is associated with priming and perpetuation of hepatic CD4+ T cell responses. Sci. Transl. Med. 18, eadx1523 (2026).","DOI":"10.1126\/scitranslmed.adx1523"},{"key":"2026060906150470000_2026.06.04.730166v1.11","first-page":"592","article-title":"Differential response of HBV envelope-specific CD4 + T cells is related to HBsAg loss after stopping nucleos(t)ide analogue therapy","volume":"78","year":"2023","journal-title":"Hepatology"},{"key":"2026060906150470000_2026.06.04.730166v1.12","doi-asserted-by":"crossref","first-page":"1352","DOI":"10.1038\/s41590-025-02199-3","article-title":"CD4+ T cells license Kupffer cells to reverse CD8+ T cell dysfunction induced by hepatocellular priming","volume":"26","year":"2025","journal-title":"Nat. Immunol"},{"key":"2026060906150470000_2026.06.04.730166v1.13","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.05.041"},{"key":"2026060906150470000_2026.06.04.730166v1.14","doi-asserted-by":"crossref","unstructured":"Chua C , Salimzadeh L , & Ma AT . IL-2 produced by HBV-specific T cells as a biomarker of viral control and predictor of response to PD-1 therapy across clinical phases of chronic hepatitis B. Hepatol. Commun. 7, e0337 (2023).","DOI":"10.1097\/HC9.0000000000000337"},{"key":"2026060906150470000_2026.06.04.730166v1.15","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2024.02.017"},{"key":"2026060906150470000_2026.06.04.730166v1.16","first-page":"34","article-title":"Intrahepatic cytotoxic CD4+ T lymphocytes and MHC class II-expressing hepatocytes are associated with functional cure in chronic hepatitis B","volume":"81","year":"2024","journal-title":"J. Hepatol"},{"key":"2026060906150470000_2026.06.04.730166v1.17","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1016\/j.jhep.2022.02.020","article-title":"Immunological biomarker discovery in cure regimens for chronic hepatitis B virus infection","volume":"77","year":"2022","journal-title":"J. Hepatol"},{"key":"2026060906150470000_2026.06.04.730166v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00549-4"},{"key":"2026060906150470000_2026.06.04.730166v1.19","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00183-09"},{"key":"2026060906150470000_2026.06.04.730166v1.20","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.79.5.3038-3051.2005"},{"key":"2026060906150470000_2026.06.04.730166v1.21","doi-asserted-by":"crossref","unstructured":"Li X , Xu L , & Lu L . Differential T-cell profiles determined by hepatitis B surface antigen decrease among people with HIV\/hepatitis B virus coinfection on treatment. J. Transl. Med. 22, 901 (2024).","DOI":"10.1186\/s12967-024-05681-y"},{"key":"2026060906150470000_2026.06.04.730166v1.22","doi-asserted-by":"crossref","unstructured":"Li X , Xu L , & Lu L . CD4(+) T cell counts and soluble programmed death-1 at baseline correlated with hepatitis B surface antigen decline in HIV\/HBV coinfection during combined antiretroviral therapy. Front. Cell. Infect. Microbiol. 13, 1178788 (2023).","DOI":"10.3389\/fcimb.2023.1178788"},{"key":"2026060906150470000_2026.06.04.730166v1.23","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1097\/HEP.0000000000000877","article-title":"HIV\/HBV coinfection remodels the immune landscape and NK cell ADCC functional responses","volume":"80","year":"2024","journal-title":"Hepatology"},{"key":"2026060906150470000_2026.06.04.730166v1.24","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2025-335461"},{"key":"2026060906150470000_2026.06.04.730166v1.25","doi-asserted-by":"publisher","DOI":"10.1136\/jitc-2025-014041"},{"key":"2026060906150470000_2026.06.04.730166v1.26","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2022.12.013"},{"key":"2026060906150470000_2026.06.04.730166v1.27","doi-asserted-by":"crossref","unstructured":"Chen X , Xu L , & Lu L . Baseline HBsAg quantitative and CD4 T cell counts are associated with HBsAg loss in people living with HIV\/HBV coinfection after combined antiretroviral therapy. Front. Cell. Infect. Microbiol. 15, 1381826 (2025).","DOI":"10.3389\/fcimb.2025.1381826"},{"key":"2026060906150470000_2026.06.04.730166v1.28","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.04.019"},{"key":"2026060906150470000_2026.06.04.730166v1.29","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2012.07.014"},{"key":"2026060906150470000_2026.06.04.730166v1.30","doi-asserted-by":"crossref","first-page":"502","DOI":"10.1016\/j.jhep.2025.03.018","article-title":"EASL Clinical Practice Guidelines on the management of hepatitis B virus infection","volume":"83","author":"European Association for the Study of the Liver","year":"2025","journal-title":"J. Hepatol"},{"key":"2026060906150470000_2026.06.04.730166v1.31","doi-asserted-by":"crossref","unstructured":"Vinikoor, M. J. & Lauer, G. M . People With Hepatitis B Virus\/HIV Coinfection Should Be Prioritized in Hepatitis B Virus Cure Research. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am. 80, 484 (2024).","DOI":"10.1093\/cid\/ciae248"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.06.04.730166","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T13:15:21Z","timestamp":1781010921000},"score":1,"resource":{"primary":{"URL":"http:\/\/biorxiv.org\/lookup\/doi\/10.64898\/2026.06.04.730166"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,6,6]]},"references-count":31,"URL":"https:\/\/doi.org\/10.64898\/2026.06.04.730166","relation":{},"subject":[],"published":{"date-parts":[[2026,6,6]]},"subtype":"preprint"}}