{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T06:30:30Z","timestamp":1786516230917,"version":"build-2736575974"},"reference-count":45,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T00:00:00Z","timestamp":1786492800000},"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:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Immunological non-responders (INRs) and immunological responders (IRs) exhibit distinct patterns of immune reconstitution despite suppressive antiretroviral therapy (ART); however, the genetic characteristics of the HIV-1 reservoir in these groups remain poorly understood. This study investigates the landscape of HIV-1 proviruses in INRs and IRs, and its potential association with immune reconstitution.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Peripheral blood mononuclear cells (PBMCs) from 10 ART-treated INRs and 10 IRs were analyzed using near-full-length HIV-1 DNA amplification and PacBio third-generation sequencing to characterize genetically intact and defective proviral genomes. Intact open reading frames (ORFs) were further inferred using the CFEIntact tool.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared with IRs, INRs had a higher total proviral genome per 10\n                      <jats:sup>6<\/jats:sup>\n                      PBMCs, although the difference did not reach statistically significance. INRs also displayed a significantly higher level of intact proviral genomes per 10\n                      <jats:sup>6<\/jats:sup>\n                      PBMCs and a trend toward a higher proportion of intact sequences. Defective proviruses remained the predominant component of the reservoir in both groups and were broadly comparable in number and composition. In both cohorts, proviral defects were more frequently observed in the 3\u2032 half of the genome.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Our study reveals a distinct proviral landscape in ART-treated INRs, characterized by elevated levels of intact proviral genomes. These observations suggest that the intact component of the reservoir may represent a clinically relevant feature of incomplete immune reconstitution, and provide a rationale for further studies of reservoir-directed interventions in this population.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1804632","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T05:54:58Z","timestamp":1786514098000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Genomic landscape of HIV-1 proviruses in ART-treated immunological non-responders"],"prefix":"10.3389","volume":"17","author":[{"given":"Shengquan","family":"Tang","sequence":"first","affiliation":[{"name":"Department of Infectious Diseases, Chongqing Public Health Medical Center","place":["Chongqing, China"]},{"name":"Basic Medicine College, Chongqing Medical University","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yue","family":"Wang","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Highly Pathogenic Microbes, Chongqing Research Center for Disease Prevention and Public Health, Chongqing Center for Disease Control and Prevention (Chongqing Academy of Preventive Medicine)","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanqiu","family":"Lu","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Chongqing Public Health Medical Center","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhen","family":"Tong","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Highly Pathogenic Microbes, Chongqing Research Center for Disease Prevention and Public Health, Chongqing Center for Disease Control and Prevention (Chongqing Academy of Preventive Medicine)","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiahui","family":"Guo","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, MOE Key Laboratory of Tumor Molecular Biology, College of Life Science and Technology, Jinan University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yizhi","family":"Cui","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, MOE Key Laboratory of Tumor Molecular Biology, College of Life Science and Technology, Jinan University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vijay","family":"Harypursat","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Chongqing Public Health Medical Center","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yemiao","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Chongqing Public Health Medical Center","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Ouyang","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Chongqing Public Health Medical Center","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huan","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Chongqing Public Health Medical Center","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tong","family":"Wang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, MOE Key Laboratory of Tumor Molecular Biology, College of Life Science and Technology, Jinan University","place":["Guangzhou, Guangdong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Quanhua","family":"Zhou","sequence":"additional","affiliation":[{"name":"Chongqing Key Laboratory of Highly Pathogenic Microbes, Chongqing Research Center for Disease Prevention and Public Health, Chongqing Center for Disease Control and Prevention (Chongqing Academy of Preventive Medicine)","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaokai","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Infectious Diseases, Chongqing Public Health Medical Center","place":["Chongqing, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,12]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1186\/s12977-022-00601-8","article-title":"Defective HIV-1 genomes and their potential impact on HIV pathogenesis","volume":"19","author":"Kuniholm","year":"2022","journal-title":"Retrovirology"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/v16050751","article-title":"Chronic HIV transcription, translation, and persistent inflammation","volume":"16","author":"Kilroy","year":"2024","journal-title":"Viruses"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1080\/22221751.2021.2017755","article-title":"Immune reconstruction effectiveness of combination antiretroviral therapy for HIV-1 CRF01_AE cluster 1 and 2 infected individuals","volume":"11","author":"Li","year":"2022","journal-title":"Emerg Microbes Infect"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0156099","article-title":"Discordant immune response with antiretroviral therapy in HIV-1: a systematic review of clinical outcomes","volume":"11","author":"Kelly","year":"2016","journal-title":"PloS One"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/nm.4156","article-title":"Defective proviruses rapidly accumulate during acute HIV-1 infection","volume":"22","author":"Bruner","year":"2016","journal-title":"Nat Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20231511","article-title":"CD4+ T cells with latent HIV-1 have reduced proliferative responses to T cell receptor stimulation","volume":"221","author":"Kufera","year":"2024","journal-title":"J Exp Med"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2013.09.020","article-title":"Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure","volume":"155","author":"Ho","year":"2013","journal-title":"Cell"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1003174","article-title":"Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies","volume":"9","author":"Eriksson","year":"2013","journal-title":"PloS Pathog"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1917876117","article-title":"Defective HIV-1 proviruses produce viral proteins","volume":"117","author":"Imamichi","year":"2020","journal-title":"Proc Natl Acad Sci USA"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1016\/j.jinf.2024.106151","article-title":"Transcriptomic crosstalk between viral and host factors drives aberrant homeostasis of T-cell proliferation and cell death in HIV-infected immunological non-responders","volume":"88","author":"Tang","year":"2024","journal-title":"J Infect"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-0716-1871-4_23","article-title":"Near-full-length single-genome HIV-1 DNA sequencing","volume":"2407","author":"Lee","year":"2022","journal-title":"Methods Mol Biol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"2737","DOI":"10.1038\/s41467-019-10659-2","article-title":"HIV-1 DNA sequence diversity and evolution during acute subtype C infection","volume":"10","author":"Lee","year":"2019","journal-title":"Nat Commun"},{"key":"B13","doi-asserted-by":"publisher","first-page":"5480","DOI":"10.1038\/s41467-024-48985-9","article-title":"HIV-1 subtype A1, D, and recombinant proviral genome landscapes during long-term suppressive therapy","volume":"15","author":"Lee","year":"2024","journal-title":"Nat Commun"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0011345","article-title":"Dynamics of HIV-1 quasispecies during antiviral treatment dissected using ultra-deep pyrosequencing","volume":"5","author":"Hedskog","year":"2010","journal-title":"PloS One"},{"key":"B15","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1111\/hiv.13253","article-title":"Pretreatment drug resistance in people living with HIV: a large retrospective cohort study in Chongqing, China","author":"Liu","year":"2022","journal-title":"HIV Med"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2023.104954","article-title":"Intact proviruses are enriched in the colon and associated with PD-1+TIGIT- mucosal CD4+ T cells of people with HIV-1 on antiretroviral therapy","volume":"100","author":"Vellas","year":"2024","journal-title":"EBioMedicine"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-019-0898-8","article-title":"A quantitative approach for measuring the reservoir of latent HIV-1 proviruses","volume":"566","author":"Bruner","year":"2019","journal-title":"Nature"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1089\/AID.2012.0243","article-title":"Short communication: HIV type 1 subtype BF leads to faster CD4+ T cell loss compared to subtype B","volume":"30","author":"Tarosso","year":"2014","journal-title":"AIDS Res Hum Retroviruses"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.ebiom.2024.105338","article-title":"HIV-1-DNA\/RNA and immunometabolism in monocytes: contribution to the chronic immune activation and inflammation in people with HIV-1","volume":"108","author":"Mu\u00f1oz-Muela","year":"2024","journal-title":"EBioMedicine"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiae009","article-title":"Transcriptionally active defective HIV-1 proviruses and their association with immunological nonresponse to antiretroviral therapy","volume":"229","author":"Scrimieri","year":"2024","journal-title":"J Infect Dis"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1186\/1742-4690-10-41","article-title":"Cell-associated HIV RNA: a dynamic biomarker of viral persistence","volume":"10","author":"Pasternak","year":"2013","journal-title":"Retrovirology"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1609057113","article-title":"Defective HIV-1 proviruses produce novel protein-coding RNA species in HIV-infected patients on combination antiretroviral therapy","volume":"113","author":"Imamichi","year":"2016","journal-title":"Proc Natl Acad Sci USA"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0007658","article-title":"HIV-1 residual viremia correlates with persistent T-cell activation in poor immunological responders to combination antiretroviral therapy","volume":"4","author":"Mavigner","year":"2009","journal-title":"PloS One"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2021.663843","article-title":"Residual viremia is linked to a specific immune activation profile in HIV-1-infected adults under efficient antiretroviral therapy","volume":"12","author":"Younas","year":"2021","journal-title":"Front Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1097\/00126334-200306010-00002","article-title":"Incomplete CD4 T cell recovery in HIV-1 infection after 12 months of highly active antiretroviral therapy is associated with ongoing increased CD4 T cell activation and turnover","volume":"33","author":"Anthony","year":"2003","journal-title":"J Acquir Immune Defic Syndr"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.clim.2006.04.570","article-title":"Low CD4+ T-cell counts in HIV patients receiving effective antiretroviral therapy are associated with CD4+ T-cell activation and senescence but not with lower effector memory T-cell function","volume":"120","author":"Fernandez","year":"2006","journal-title":"Clin Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1371\/journal.ppat.1005761","article-title":"CD4+ T cells expressing PD-1, TIGIT and LAG-3 contribute to HIV persistence during ART","volume":"12","author":"Fromentin","year":"2016","journal-title":"PloS Pathog"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1097\/QAD.0000000000002465","article-title":"High levels of genetically intact HIV in HLA-DR+ memory T cells indicates their value for reservoir studies","volume":"34","author":"Horsburgh","year":"2020","journal-title":"AIDS"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.132997","article-title":"Differential decay of intact and defective proviral DNA in HIV-1-infected individuals on suppressive antiretroviral therapy","volume":"5","author":"Peluso","year":"2020","journal-title":"JCI Insight"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiaa532","article-title":"Selective decay of intact HIV-1 proviral DNA on antiretroviral therapy","volume":"223","author":"Gandhi","year":"2021","journal-title":"J Infect Dis"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.3390\/v12020136","article-title":"Dynamic shifts in the HIV proviral landscape during long term combination antiretroviral therapy: implications for persistence and control of HIV infections","volume":"12","author":"Anderson","year":"2020","journal-title":"Viruses"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-021-01590-5","article-title":"Research priorities for an HIV cure: International AIDS Society Global Scientific Strategy 2021","volume":"27","author":"Deeks","year":"2021","journal-title":"Nat Med"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiad039","article-title":"Varied patterns of decay of intact human immunodeficiency virus type 1 proviruses over 2 decades of antiretroviral therapy","volume":"227","author":"Gandhi","year":"2023","journal-title":"J Infect Dis"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2015.10","article-title":"The multifaceted role of CD4(+) T cells in CD8(+) T cell memory","volume":"16","author":"Laidlaw","year":"2016","journal-title":"Nat Rev Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.3390\/ijms22020523","article-title":"Role of CD4+ T cells in the control of viral infections: recent advances and open questions","volume":"22","author":"Kervevan","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0171658","article-title":"Systematic review of statistically-derived models of immunological response in HIV-infected adults on antiretroviral therapy in Sub-Saharan Africa","volume":"12","author":"Sempa","year":"2017","journal-title":"PloS One"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1172\/JCI93289","article-title":"Clonal expansion of genome-intact HIV-1 in functionally polarized Th1 CD4+ T cells","volume":"127","author":"Lee","year":"2017","journal-title":"J Clin Invest"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1016\/j.celrep.2017.09.081","article-title":"Identification of genetically intact HIV-1 proviruses in specific CD4+ T cells from effectively treated participants","volume":"21","author":"Hiener","year":"2017","journal-title":"Cell Rep"},{"key":"B39","doi-asserted-by":"publisher","first-page":"494","DOI":"10.1016\/j.chom.2017.03.008","article-title":"Defective HIV-1 proviruses are expressed and can be recognized by cytotoxic T lymphocytes, which shape the proviral landscape","volume":"21","author":"Pollack","year":"2017","journal-title":"Cell Host Microbe"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiab121","article-title":"Gag p24 is a marker of human immunodeficiency virus expression in tissues and correlates with immune response","volume":"224","author":"Wu","year":"2021","journal-title":"J Infect Dis"},{"key":"B41","doi-asserted-by":"publisher","first-page":"79","DOI":"10.1186\/s12977-018-0462-x","article-title":"The role of exosomal transport of viral agents in persistent HIV pathogenesis","volume":"15","author":"Patters","year":"2018","journal-title":"Retrovirology"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1182\/blood.v96.9.2951","article-title":"Mechanisms of HIV-associated lymphocyte apoptosis","volume":"96","author":"Badley","year":"2000","journal-title":"Blood"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1097\/COH.0000000000000849","article-title":"Persistent HIV-1 transcription during ART: time to reassess its significance","volume":"19","author":"Fombellida-Lopez","year":"2024","journal-title":"Curr Opin HIV AIDS"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abl4097","article-title":"Signatures of immune selection in intact and defective proviruses distinguish HIV-1 elite controllers","volume":"13","author":"Lian","year":"2021","journal-title":"Sci Transl Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-2651-8","article-title":"Distinct viral reservoirs in individuals with spontaneous control of HIV-1","volume":"585","author":"Jiang","year":"2020","journal-title":"Nature"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1804632\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T05:54:59Z","timestamp":1786514099000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2026.1804632\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,12]]},"references-count":45,"alternative-id":["10.3389\/fimmu.2026.1804632"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2026.1804632","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,12]]},"article-number":"1804632"}}