{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T01:40:42Z","timestamp":1772156442345,"version":"3.50.1"},"posted":{"date-parts":[[2025,4,3]]},"group-title":"Infectious Diseases (except HIV\/AIDS)","reference-count":52,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T00:00:00Z","timestamp":1743638400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2025,4,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Objective<\/jats:title>\n                  <jats:p>\n                    Chronic HBV infection disproportionately affects people living with HIV, who are often excluded from functional cure studies. This study investigates CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell profiles in HBV mono-infection versus HBV\/HIV co-infection, examining the impact of long-term therapy on virus-specific responses with the goal of informing therapeutic strategies for immune restoration.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Design<\/jats:title>\n                  <jats:p>\n                    We analysed CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell responses in 61 participants (HBV n=20, HBV\/HIV n=20, HIV n=21), on suppressive antiviral therapy. We assessed transcriptomic and proteomic profiles, focusing on exhaustion markers alongside virus-specific functional capabilities.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    Transcriptomic analysis revealed a distinct signature in co-infection, with upregulation of genes associated with TCR signaling, inhibitory pathways and progenitor-exhausted markers (\n                    <jats:italic>XCL2, TCF7, PDCD1, IL7R<\/jats:italic>\n                    ). This gene profile scored highly for a precursor exhausted (Tpex) CD8+ T cell signature, reflecting a \"stemness\" programme that maintains plasticity despite chronic antigen exposure. Proteomic analysis confirmed higher frequencies of precursor exhausted TCF-1\n                    <jats:sup>+<\/jats:sup>\n                    CD127\n                    <jats:sup>+<\/jats:sup>\n                    PD-1\n                    <jats:sup>+<\/jats:sup>\n                    CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cells in co-infection, while HBV mono-infection showed predominance of terminally exhausted Tox\n                    <jats:sup>high<\/jats:sup>\n                    TCF-1\n                    <jats:sup>-<\/jats:sup>\n                    CD127\n                    <jats:sup>-<\/jats:sup>\n                    cells. These differences correlated with more robust, polyfunctional HBV-specific responses in co-infection against surface and core antigens. Lower HBsAg levels and longer treatment duration in co-infection associated positively with Tpex populations and functional responses and inversely with terminal exhaustion.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>\n                    Our findings demonstrate that individuals with well-controlled HBV\/HIV co-infection maintain more robust CD8\n                    <jats:sup>+<\/jats:sup>\n                    T cell responses with preserved stem-like properties supporting ongoing antiviral function. These results underscore the benefits of early antiretroviral intervention and the need for tailored immune-modulatory therapies to restore antiviral functionality in these diverse patient populations.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>WHAT IS ALREADY KNOWN ON THIS TOPIC<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Chronic hepatitis B virus (HBV) infection is marked by a progressive dysfunction of CD8\u207a T cells, which are crucial for antiviral responses. Traditionally these responses were thought to be more severely impacted in people with HBV\/HIV co-infection.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>WHAT THIS STUDY ADDS<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>Our study provides new insights into the heterogeneous functional profiles of HBV-specific CD8\u207a T cells in people with HBV and HBV\/HIV co-infection in the current antiretroviral therapy (ART) era.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>People living with HBV\/HIV co-infection suppressed on antivirals have a higher prevalence of precursor exhausted CD8\u207a T cells (Tpex), alongside more effective antiviral responses when compared to those with HBV mono-infection.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Our data demonstrate intrinsic differences in T cell profiles, revealing a paradoxical increase in terminally exhausted CD8\u207a T cells in people with HBV mono-infection.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>HOW THIS STUDY MIGHT AFFECT RESEARCH, PRACTICE OR POLICY<\/jats:title>\n                  <jats:list list-type=\"bullet\">\n                    <jats:list-item>\n                      <jats:p>By providing a clearer understanding of CD8\u207a T cell dynamics in HBV mono-infection and HBV\/HIV co-infection, our findings could inform the design of tailored immunotherapies aimed at revitalising antiviral responses.<\/jats:p>\n                    <\/jats:list-item>\n                    <jats:list-item>\n                      <jats:p>Furthermore, this research may influence practices regarding clinical management emphasising the need for early intervention strategies and individualised approaches tailored to T cell profiles rather than solely based on infection status.<\/jats:p>\n                    <\/jats:list-item>\n                  <\/jats:list>\n                <\/jats:sec>","DOI":"10.1101\/2025.03.30.25324898","type":"posted-content","created":{"date-parts":[[2025,4,3]],"date-time":"2025-04-03T19:00:16Z","timestamp":1743706816000},"source":"Crossref","is-referenced-by-count":0,"title":["Stem-like CD8+ T cells preserve HBV-specific responses in HBV\/HIV co-infection"],"prefix":"10.64898","author":[{"given":"Jay","family":"Preechanukul","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Aljawharah","family":"Alrubayyi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bo","family":"Sun","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edward","family":"Arbe-Barnes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jonida","family":"Kokici","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frances","family":"Gorou","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarun","family":"Prasitdumrong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kelly A.S.","family":"da Costa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natasha","family":"Fisher-Pearson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Noshin","family":"Hussain","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephanie","family":"Kucykowicz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Indrajit","family":"Ghosh","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fiona","family":"Burns","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sabine","family":"Kinloch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pedro","family":"Simoes","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sanjay","family":"Bhagani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Patrick T F","family":"Kennedy","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mala K","family":"Maini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rachael","family":"Bashford-Rogers","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Upkar S","family":"Gill","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9281-5471","authenticated-orcid":false,"given":"Dimitra","family":"Peppa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"key":"2025040501451907000_2025.03.30.25324898v1.1","doi-asserted-by":"publisher","DOI":"10.1111\/jvh.13217"},{"key":"2025040501451907000_2025.03.30.25324898v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-021-00549-4"},{"key":"2025040501451907000_2025.03.30.25324898v1.3","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.02844-06"},{"key":"2025040501451907000_2025.03.30.25324898v1.4","doi-asserted-by":"publisher","DOI":"10.1002\/hep.24249"},{"key":"2025040501451907000_2025.03.30.25324898v1.5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0047648"},{"key":"2025040501451907000_2025.03.30.25324898v1.6","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2022-327202"},{"key":"2025040501451907000_2025.03.30.25324898v1.7","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2016.06.078"},{"key":"2025040501451907000_2025.03.30.25324898v1.8","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2020.04.019"},{"key":"2025040501451907000_2025.03.30.25324898v1.9","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000001574"},{"key":"2025040501451907000_2025.03.30.25324898v1.10","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00183-09"},{"key":"2025040501451907000_2025.03.30.25324898v1.11","doi-asserted-by":"publisher","DOI":"10.1086\/379896"},{"key":"2025040501451907000_2025.03.30.25324898v1.12","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiz450"},{"key":"2025040501451907000_2025.03.30.25324898v1.13","doi-asserted-by":"publisher","DOI":"10.1097\/QAI.0000000000002386"},{"key":"2025040501451907000_2025.03.30.25324898v1.14","doi-asserted-by":"publisher","DOI":"10.1097\/HEP.0000000000000877"},{"key":"2025040501451907000_2025.03.30.25324898v1.15","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-022-01219-w"},{"key":"2025040501451907000_2025.03.30.25324898v1.16","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2016.07.021"},{"key":"2025040501451907000_2025.03.30.25324898v1.17","doi-asserted-by":"publisher","DOI":"10.1038\/nature19330"},{"key":"2025040501451907000_2025.03.30.25324898v1.18","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-024-01097-3"},{"key":"2025040501451907000_2025.03.30.25324898v1.19","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2021.04.048"},{"key":"2025040501451907000_2025.03.30.25324898v1.20","doi-asserted-by":"publisher","DOI":"10.1016\/j.cels.2020.05.010"},{"key":"2025040501451907000_2025.03.30.25324898v1.21","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2023.11.026"},{"key":"2025040501451907000_2025.03.30.25324898v1.22","doi-asserted-by":"publisher","DOI":"10.1186\/s13073-016-0384-y"},{"key":"2025040501451907000_2025.03.30.25324898v1.23","doi-asserted-by":"publisher","DOI":"10.1038\/s41587-021-01033-z"},{"key":"2025040501451907000_2025.03.30.25324898v1.24","doi-asserted-by":"publisher","DOI":"10.1126\/science.abe6474"},{"key":"2025040501451907000_2025.03.30.25324898v1.25","doi-asserted-by":"publisher","DOI":"10.1101\/2024.11.06.622266"},{"key":"2025040501451907000_2025.03.30.25324898v1.26","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-021-26137-7"},{"key":"2025040501451907000_2025.03.30.25324898v1.27","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00262.2014"},{"key":"2025040501451907000_2025.03.30.25324898v1.28","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbamem.2013.05.004"},{"key":"2025040501451907000_2025.03.30.25324898v1.29","doi-asserted-by":"publisher","DOI":"10.1177\/117727190700200023"},{"key":"2025040501451907000_2025.03.30.25324898v1.30","doi-asserted-by":"publisher","DOI":"10.15252\/embr.201643103"},{"key":"2025040501451907000_2025.03.30.25324898v1.31","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2025.01.001"},{"key":"2025040501451907000_2025.03.30.25324898v1.32","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.2001348"},{"key":"2025040501451907000_2025.03.30.25324898v1.33","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-1325-x"},{"key":"2025040501451907000_2025.03.30.25324898v1.34","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-019-0312-6"},{"key":"2025040501451907000_2025.03.30.25324898v1.35","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1100102"},{"key":"2025040501451907000_2025.03.30.25324898v1.36","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-020-00817-w"},{"key":"2025040501451907000_2025.03.30.25324898v1.37","doi-asserted-by":"publisher","DOI":"10.1053\/j.gastro.2019.01.035"},{"key":"2025040501451907000_2025.03.30.25324898v1.38","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.136648"},{"key":"2025040501451907000_2025.03.30.25324898v1.39","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2018-316641"},{"key":"2025040501451907000_2025.03.30.25324898v1.40","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms15050"},{"key":"2025040501451907000_2025.03.30.25324898v1.41","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08451-4"},{"key":"2025040501451907000_2025.03.30.25324898v1.42","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-024-08562-y"},{"key":"2025040501451907000_2025.03.30.25324898v1.43","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2020-322404"},{"key":"2025040501451907000_2025.03.30.25324898v1.44","doi-asserted-by":"publisher","DOI":"10.1136\/egastro-2024-100067"},{"key":"2025040501451907000_2025.03.30.25324898v1.45","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1007797"},{"key":"2025040501451907000_2025.03.30.25324898v1.46","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.02.008"},{"key":"2025040501451907000_2025.03.30.25324898v1.47","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhepr.2019.07.007"},{"key":"2025040501451907000_2025.03.30.25324898v1.48","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2022.103840"},{"key":"2025040501451907000_2025.03.30.25324898v1.49","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abl3836"},{"key":"2025040501451907000_2025.03.30.25324898v1.50","doi-asserted-by":"publisher","DOI":"10.1172\/JCI157549"},{"key":"2025040501451907000_2025.03.30.25324898v1.51","doi-asserted-by":"publisher","DOI":"10.1016\/j.isci.2023.108666"},{"key":"2025040501451907000_2025.03.30.25324898v1.52","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.ado3032"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1101\/2025.03.30.25324898","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T20:32:51Z","timestamp":1768509171000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.1101\/2025.03.30.25324898"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,3]]},"references-count":52,"URL":"https:\/\/doi.org\/10.1101\/2025.03.30.25324898","relation":{"has-review":[{"id-type":"doi","id":"10.1162\/2e3983f5.7e00d990","asserted-by":"object"},{"id-type":"doi","id":"10.1162\/2e3983f5.038ea44e","asserted-by":"object"}]},"subject":[],"published":{"date-parts":[[2025,4,3]]},"subtype":"preprint"}}