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R+D+I","award":["RD16\/0025\/0019"],"award-info":[{"award-number":["RD16\/0025\/0019"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background: The immunological factors associated with long-term hepatitis C virus (HCV)-specific humoral immunity after cure remain uncharacterized, particularly in people with HIV (PWH). This study investigated T-cell immunophenotypes and plasma biomarkers associated with anti-E2 binding (HCV-E2Abs) and neutralizing antibody (HCV-nAbs) titers 5 years after achieving sustained virologic response (SVR). Methods: This cross-sectional study analyzed 64 PWH with cured HCV and prior advanced fibrosis. We quantified plasma antibody titers against 5 HCV genotypes, T-cell phenotypes (n = 58), and plasma biomarkers (n = 50). Associations were assessed using Generalized Linear Models (gamma distribution, log-link function) adjusted for clinical confounders, reporting adjusted Arithmetic Mean Ratios (aAMRs) and false discovery rate (FDR)-corrected q-values. Results: Higher frequencies of CD4+ T-cell activation (CD38+; aAMR = 1.58; q = 0.028) and soluble CD27 levels (aAMR = 1.46; q = 0.038) were associated with higher HCV-E2Abs titers. In contrast, memory T-cell activation across CD4+ and CD8+ compartments (HLA-DR+ and CD38+; all q &lt; 0.10) and elevated soluble immune checkpoints (sCD28, sPD-L2, sLAG-3, sCTLA-4; all q &lt; 0.10) were associated with preserved HCV-nAbs titers. Conversely, a higher frequency of na\u00efve CD8+ T-cells was associated with lower neutralization capacity (aAMR = 0.41; q = 0.042). Regarding inflammatory markers, soluble TNF-RI was positively associated with neutralizing titers (aAMR = 1.44; q = 0.019), whereas IL-18 was inversely associated (aAMR = 0.53; q = 0.019). Conclusions: Specific activated T-cell subsets, checkpoint shedding, and selective inflammatory signals were associated with higher long-term HCV-nAbs titers in PWH. In contrast, higher frequencies of na\u00efve CD8+ T-cells and elevated IL-18 levels were associated with reduced neutralizing capacity.<\/jats:p>","DOI":"10.3390\/ph19060854","type":"journal-article","created":{"date-parts":[[2026,6,4]],"date-time":"2026-06-04T01:08:02Z","timestamp":1780535282000},"page":"854","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Immune Factors Linked to Long-Term HCV Humoral Memory Five Years After Cure in People with HIV: A Cross-Sectional Study"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9253-1631","authenticated-orcid":false,"given":"Rafael","family":"Amigot-S\u00e1nchez","sequence":"first","affiliation":[{"name":"Unidad de Infecci\u00f3n Viral e Inmunidad, Centro Nacional de Microbiolog\u00eda (CNM), Instituto de Salud Carlos III (ISCIII), 28220 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), 28220 Madrid, Spain"},{"name":"Escuela de Doctorado de Microbiolog\u00eda, Universidad Aut\u00f3noma de Madrid, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8053-6045","authenticated-orcid":false,"given":"Daniel","family":"Sep\u00falveda-Crespo","sequence":"additional","affiliation":[{"name":"Unidad de Infecci\u00f3n Viral e Inmunidad, Centro Nacional de Microbiolog\u00eda (CNM), Instituto de Salud Carlos III (ISCIII), 28220 Madrid, Spain"},{"name":"Centro de Investigaci\u00f3n Biom\u00e9dica en Red en Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III (ISCIII), 28220 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6262-9344","authenticated-orcid":false,"given":"Rub\u00e9n","family":"Martin Escolano","sequence":"additional","affiliation":[{"name":"Unidad de Infecci\u00f3n 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(2020). EASL recommendations on treatment of hepatitis C: Final update of the series. J. Hepatol., 73, 1170\u20131218.","DOI":"10.1016\/j.jhep.2020.08.018"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1085","DOI":"10.1016\/S0140-6736(23)01320-X","article-title":"Hepatitis C","volume":"402","author":"Martinello","year":"2023","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1186\/s12929-021-00718-6","article-title":"HCV eradication with IFN-based therapy does not completely restore gene expression in PBMCs from HIV\/HCV-coinfected patients","volume":"28","author":"Brochado","year":"2021","journal-title":"J. Biomed. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1038\/s41575-021-00520-7","article-title":"Cirrhosis-associated immune dysfunction","volume":"19","author":"Albillos","year":"2022","journal-title":"Nat. Rev. Gastroenterol. 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