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In this study, we analyzed 96 plasma proteome arrays from chronic untreated HIV-1\u2013infected individuals using the classificatory random forest approach to discriminate between uncontrolled disease (plasma viral load [pVL] &amp;gt;50,000 RNA copies\/ml; CD4 counts 283 cells\/mm3, n = 47) and relatively controlled disease (pVL &amp;lt;10,000 RNA copies\/ml; CD4 counts 657 cells\/mm3, n = 49). Our analysis highlighted the TNF molecule\u2019s relevance, in particular, TL1A (TNFSF15) and its cognate DR3 (TNFSRF25), both of which increased in the relative virus control phenotype. DR3 levels (in plasma and PBMCs) were validated in unrelated cohorts (including long-term nonprogressors), thus confirming their independence from CD4 counts and pVL. Further analysis in combined antiretroviral treatment (cART)\u2013treated individuals with a wide range of CD4 counts (137\u20131835 cells\/mm3) indicated that neither TL1A nor DR3 levels reflected recovery of CD4 counts with cART. Interestingly, in cART-treated individuals, plasma TL1A levels correlated with regulatory T cell frequencies, whereas soluble DR3 was strongly associated with the abundance of effector HLA-DR+CD8+ T cells. A positive correlation was also observed between plasma DR3 levels and the HIV-1\u2013specific T cell responses. In vitro, costimulation of PBMC with DR3-specific mAb increased the magnitude of HIV-1\u2013specific responses. Finally, in splenocytes of DNA.HTI-vaccinated mice, costimulation of HTI peptides and a DR3 agonist (4C12) intensified the magnitude of T cell responses by 27%. These data describe the role of the TL1A\u2013DR3 axis in the natural control of HIV-1 infection and point to the use of DR3 agonists in HIV-1 vaccine regimens.<\/jats:p>","DOI":"10.4049\/jimmunol.2000933","type":"journal-article","created":{"date-parts":[[2020,11,11]],"date-time":"2020-11-11T19:35:34Z","timestamp":1605123334000},"page":"3348-3357","source":"Crossref","is-referenced-by-count":3,"title":["TL1A\u2013DR3 Plasma Levels Are Predictive of HIV-1 Disease Control, and DR3 Costimulation Boosts HIV-1\u2013Specific T Cell Responses"],"prefix":"10.1093","volume":"205","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2714-9097","authenticated-orcid":false,"given":"Bruna","family":"Oriol-Tordera","sequence":"first","affiliation":[{"name":"Institut de Recerca de la Sida IrsiCaixa, Hospital Universitari Germans Trias i Pujol , Badalona, 08916 Barcelona ,","place":["Spain"]},{"name":"Departament de Biologia Cellular, de Fisiologia i d'Immunologia, Universitat Aut\u00f2noma de Barcelona, Cerdanyola del Vall\u00e8s , 08193 Barcelona ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alex","family":"Olvera","sequence":"additional","affiliation":[{"name":"Institut de Recerca de la Sida IrsiCaixa, Hospital Universitari Germans Trias i Pujol , Badalona, 08916 Barcelona ,","place":["Spain"]},{"name":"Universitat de Vic - Universitat Central de Catalunya , Vic, 08500 Barcelona ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4034-5738","authenticated-orcid":false,"given":"Clara","family":"Duran-Castells","sequence":"additional","affiliation":[{"name":"Institut de Recerca de la Sida IrsiCaixa, Hospital Universitari Germans Trias i Pujol , Badalona, 08916 Barcelona ,","place":["Spain"]},{"name":"Departament de Biologia Cellular, de Fisiologia i d'Immunologia, Universitat Aut\u00f2noma de Barcelona, Cerdanyola del Vall\u00e8s , 08193 Barcelona ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anuska","family":"Llano","sequence":"additional","affiliation":[{"name":"Institut de Recerca de la Sida IrsiCaixa, Hospital Universitari Germans Trias i Pujol , Badalona, 08916 Barcelona ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Beatriz","family":"Mothe","sequence":"additional","affiliation":[{"name":"Institut de Recerca de la Sida IrsiCaixa, Hospital Universitari Germans Trias i Pujol , Badalona, 08916 Barcelona ,","place":["Spain"]},{"name":"Universitat de Vic - Universitat Central de Catalunya , Vic, 08500 Barcelona ,","place":["Spain"]},{"name":"Fundaci\u00f3 Lluita contra la Sida i les Malalties Infeccioses, Servei de Malalties Infecciones Hospital Universitari Germans Trias i Pujol , Badalona, 08916 Barcelona ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3326-151X","authenticated-orcid":false,"given":"Marta","family":"Massanella","sequence":"additional","affiliation":[{"name":"Institut de Recerca de la Sida IrsiCaixa, Hospital Universitari Germans Trias i Pujol , Badalona, 08916 Barcelona ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Judith","family":"Dalmau","sequence":"additional","affiliation":[{"name":"Institut de Recerca de la Sida IrsiCaixa, Hospital Universitari Germans Trias i Pujol , Badalona, 08916 Barcelona ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6238-8504","authenticated-orcid":false,"given":"Carmela","family":"Ganoza","sequence":"additional","affiliation":[{"name":"Asociaci\u00f3n Civil Impacta Salud y Educacion , Lima 15063 ,","place":["Peru"]},{"name":"Facultad de Medicina Alberto Hurtado de la Universidad Peruana Cayetano Heredia, San Mart\u00edn de Porres , Lima 15102 ,","place":["Peru"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6020-8266","authenticated-orcid":false,"given":"Jorge","family":"Sanchez","sequence":"additional","affiliation":[{"name":"Asociaci\u00f3n Civil Impacta Salud y Educacion , Lima 15063 ,","place":["Peru"]},{"name":"Department of Global Health, University of Washington , Seattle, WA 98195"},{"name":"Centro de Investigaciones Tecnol\u00f3gicas, Biom\u00e9dicas y Medioambientales , Bellavista, Lima 07006 ,","place":["Peru"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9334-415X","authenticated-orcid":false,"given":"Maria Luz","family":"Calle","sequence":"additional","affiliation":[{"name":"Universitat de Vic - Universitat Central de Catalunya , Vic, 08500 Barcelona ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Bonaventura","family":"Clotet","sequence":"additional","affiliation":[{"name":"Institut de Recerca de la Sida IrsiCaixa, Hospital Universitari Germans Trias i Pujol , Badalona, 08916 Barcelona ,","place":["Spain"]},{"name":"Universitat de Vic - Universitat Central de Catalunya , Vic, 08500 Barcelona ,","place":["Spain"]},{"name":"Fundaci\u00f3 Lluita contra la Sida i les Malalties Infeccioses, Servei de Malalties Infecciones Hospital Universitari Germans Trias i Pujol , Badalona, 08916 Barcelona ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4916-2129","authenticated-orcid":false,"given":"Javier","family":"Martinez-Picado","sequence":"additional","affiliation":[{"name":"Institut de Recerca de la Sida IrsiCaixa, Hospital Universitari Germans Trias i Pujol , Badalona, 08916 Barcelona ,","place":["Spain"]},{"name":"Universitat de Vic - Universitat Central de Catalunya , Vic, 08500 Barcelona ,","place":["Spain"]},{"name":"Instituci\u00f3 Catalana de Recerca i Estudis Avan\u00e7ats , 08010 Barcelona ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5298-1734","authenticated-orcid":false,"given":"Eug\u00e8nia","family":"Negredo","sequence":"additional","affiliation":[{"name":"Universitat de Vic - Universitat Central de Catalunya , Vic, 08500 Barcelona ,","place":["Spain"]},{"name":"Fundaci\u00f3 Lluita contra la Sida i les Malalties Infeccioses, Servei de Malalties Infecciones Hospital Universitari Germans Trias i Pujol , Badalona, 08916 Barcelona ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juli\u00e0","family":"Blanco","sequence":"additional","affiliation":[{"name":"Institut de Recerca de la Sida IrsiCaixa, Hospital Universitari Germans Trias i Pujol , Badalona, 08916 Barcelona ,","place":["Spain"]},{"name":"Universitat de Vic - Universitat Central de Catalunya , Vic, 08500 Barcelona ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dennis","family":"Hartigan-O'Connor","sequence":"additional","affiliation":[{"name":"Department of Medical Microbiology and Immunology, University of California , Davis, Davis, CA 95616"},{"name":"California National Primate Research Center, University of California , Davis, Davis, CA 95616"},{"name":"Division of Experimental Medicine, University of California , San Francisco, San Francisco, CA 94110"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0548-5778","authenticated-orcid":false,"given":"Christian","family":"Brander","sequence":"additional","affiliation":[{"name":"Institut de Recerca de la Sida IrsiCaixa, Hospital Universitari Germans Trias i Pujol , Badalona, 08916 Barcelona ,","place":["Spain"]},{"name":"Universitat de Vic - Universitat Central de Catalunya , Vic, 08500 Barcelona ,","place":["Spain"]},{"name":"Instituci\u00f3 Catalana de Recerca i Estudis Avan\u00e7ats , 08010 Barcelona ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1899-8879","authenticated-orcid":false,"given":"Marta","family":"Ruiz-Riol","sequence":"additional","affiliation":[{"name":"Institut de Recerca de la Sida IrsiCaixa, Hospital Universitari Germans Trias i Pujol , Badalona, 08916 Barcelona ,","place":["Spain"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2020,12,15]]},"reference":[{"key":"2025030417505992500_r1","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/s41586-019-1841-8","article-title":"Why and where an HIV cure is needed and how it might be achieved","volume":"576","author":"Ndung\u2019u","year":"2019","journal-title":"Nature"},{"key":"2025030417505992500_r2","doi-asserted-by":"crossref","first-page":"859","DOI":"10.1007\/s40265-020-01322-y","article-title":"Novel approaches towards a functional cure of HIV\/AIDS. 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