Unveiling altered CD8 T-cell metabolism and homeostatic proliferation behind a low CD4/CD8 ratio in ART-suppressed HIV individuals with normal CD4 recovery

Garrido-Rodríguez, Vanesa; Bulnes-Ramos, Ángel; Olivas-Martínez, Israel; Pozo-Balado, Maria del Mar; Tejerina-Picado, Francisco; Gutiérrez, Félix; Marco-Sánchez, Cristina; Tiraboschi, Juan Manuel; Castillo-Navarro, Antonia; Bernal, Enrique; García-Guerrero, Maria C.; Puertas, Maria C.; Peraire, Joaquim; Rull, Anna; Martinez-Picado, Javier; Pacheco, Yolanda María

Unveiling altered CD8 T-cell metabolism and homeostatic proliferation behind a low CD4/CD8 ratio in ART-suppressed HIV individuals with normal CD4 recovery

Background: People living with chronic HIV (PLWH) show immune dysfunction, despite viral suppression and normal CD4 recovery, particularly those with low CD4/CD8 ratios. Subjacent cellular alterations of such a reliable marker of clinical progression remain elusive. Methods: Categorization by CD4/CD...

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Autores:	Garrido-Rodríguez, Vanesa, Bulnes-Ramos, Ángel, Olivas-Martínez, Israel, Pozo-Balado, Maria del Mar, Tejerina-Picado, Francisco, Gutiérrez, Félix, Marco-Sánchez, Cristina, Tiraboschi, Juan Manuel, Castillo-Navarro, Antonia, Bernal, Enrique, García-Guerrero, Maria C., Puertas, Maria C., Peraire, Joaquim, Rull, Anna, Martinez-Picado, Javier, Pacheco, Yolanda María
Tipo de recurso:	artículo
Fecha de publicación:	2025
País:	España
Institución:	Universidad Loyola Andalucía
Repositorio:	Brújula
OAI Identifier:	oai:repositorio.uloyola.es:20.500.12412/6894
Acceso en línea:	https://hdl.handle.net/20.500.12412/6894
Access Level:	acceso abierto
Palabra clave:	HIV-infection CD4/CD8 ratio Nadir-CD4 T cell Immunometabolism Viral reservoir Thymic output

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oai_identifier_str	oai:repositorio.uloyola.es:20.500.12412/6894
network_acronym_str	ES
network_name_str	España
repository_id_str
dc.title.none.fl_str_mv	Unveiling altered CD8 T-cell metabolism and homeostatic proliferation behind a low CD4/CD8 ratio in ART-suppressed HIV individuals with normal CD4 recovery Descubriendo alteraciones en el metabolismo de las células T CD8 y la proliferación homeostática detrás de una baja relación CD4/CD8 en individuos con VIH suprimidos por TAR con recuperación normal de CD4
title	Unveiling altered CD8 T-cell metabolism and homeostatic proliferation behind a low CD4/CD8 ratio in ART-suppressed HIV individuals with normal CD4 recovery
spellingShingle	Unveiling altered CD8 T-cell metabolism and homeostatic proliferation behind a low CD4/CD8 ratio in ART-suppressed HIV individuals with normal CD4 recovery Garrido-Rodríguez, Vanesa HIV-infection CD4/CD8 ratio Nadir-CD4 T cell Immunometabolism Viral reservoir Thymic output
title_short	Unveiling altered CD8 T-cell metabolism and homeostatic proliferation behind a low CD4/CD8 ratio in ART-suppressed HIV individuals with normal CD4 recovery
title_full	Unveiling altered CD8 T-cell metabolism and homeostatic proliferation behind a low CD4/CD8 ratio in ART-suppressed HIV individuals with normal CD4 recovery
title_fullStr	Unveiling altered CD8 T-cell metabolism and homeostatic proliferation behind a low CD4/CD8 ratio in ART-suppressed HIV individuals with normal CD4 recovery
title_full_unstemmed	Unveiling altered CD8 T-cell metabolism and homeostatic proliferation behind a low CD4/CD8 ratio in ART-suppressed HIV individuals with normal CD4 recovery
title_sort	Unveiling altered CD8 T-cell metabolism and homeostatic proliferation behind a low CD4/CD8 ratio in ART-suppressed HIV individuals with normal CD4 recovery
dc.creator.none.fl_str_mv	Garrido-Rodríguez, Vanesa Bulnes-Ramos, Ángel Olivas-Martínez, Israel Pozo-Balado, Maria del Mar Tejerina-Picado, Francisco Gutiérrez, Félix Marco-Sánchez, Cristina Tiraboschi, Juan Manuel Castillo-Navarro, Antonia Bernal, Enrique García-Guerrero, Maria C. Puertas, Maria C. Peraire, Joaquim Rull, Anna Martinez-Picado, Javier Pacheco, Yolanda María
author	Garrido-Rodríguez, Vanesa
author_facet	Garrido-Rodríguez, Vanesa Bulnes-Ramos, Ángel Olivas-Martínez, Israel Pozo-Balado, Maria del Mar Tejerina-Picado, Francisco Gutiérrez, Félix Marco-Sánchez, Cristina Tiraboschi, Juan Manuel Castillo-Navarro, Antonia Bernal, Enrique García-Guerrero, Maria C. Puertas, Maria C. Peraire, Joaquim Rull, Anna Martinez-Picado, Javier Pacheco, Yolanda María
author_role	author
author2	Bulnes-Ramos, Ángel Olivas-Martínez, Israel Pozo-Balado, Maria del Mar Tejerina-Picado, Francisco Gutiérrez, Félix Marco-Sánchez, Cristina Tiraboschi, Juan Manuel Castillo-Navarro, Antonia Bernal, Enrique García-Guerrero, Maria C. Puertas, Maria C. Peraire, Joaquim Rull, Anna Martinez-Picado, Javier Pacheco, Yolanda María
author2_role	author author author author author author author author author author author author author author author
dc.subject.none.fl_str_mv	HIV-infection CD4/CD8 ratio Nadir-CD4 T cell Immunometabolism Viral reservoir Thymic output
topic	HIV-infection CD4/CD8 ratio Nadir-CD4 T cell Immunometabolism Viral reservoir Thymic output
description	Background: People living with chronic HIV (PLWH) show immune dysfunction, despite viral suppression and normal CD4 recovery, particularly those with low CD4/CD8 ratios. Subjacent cellular alterations of such a reliable marker of clinical progression remain elusive. Methods: Categorization by CD4/CD8 ratio after three year of therapy (R < 0.8/R > 1.2, n = 28/n = 24) and post-hoc reclassification by nadir-CD4 (N ≤ 350/N > 350) were performed in PLWH achieving viral suppression and CD4 ≥ 500. CD4 T cell–associated viral reservoir, as well as metabolism-related gene expression, glucose uptake ability, relative telomere length (RTL), and thymic output for CD4 and CD8 T cells, were determined. Results: Patients with a CD4/CD8 ratio < 0.8 exhibited reduced CD8 T-cell glucose uptake ability after stimulation (p = 0.007) and trends to shorter RTL (p = 0.093) and to larger CD4-associated viral reservoir (p = 0.068) than R > 1.2. Differently, patients with nadir ≤350 exhibited altered CD4 and CD8 T-cell expression of metabolism-related genes, although no differences in glucose uptake ability, and shorter RTL in both cell subsets, but similar viral reservoir to patients with nadir >350. Remarkably, viral reservoir and both CD4 and CD8 thymic output showed inverse associations (r = −0.623, p = 0.01 and r = −0.661, p = 0.038, respectively). Conclusion: A low CD4/CD8 ratio in chronic PLWH stands on a larger viral reservoir in CD4 T cells and metabolic alterations in CD8 T cells, probably related to its exhaustion and compromised effector functionality, and thymic output could contribute to such alterations. Patients with lower nadir-CD4 showed a resting-like CD4 phenotype and a metabolically active CD8 subset, without further viral reservoir extension. Persistence of low CD4/CD8 ratio and low nadir-CD4 counts seems to rely on different immune damage.
publishDate	2025
dc.date.none.fl_str_mv	2025
dc.type.none.fl_str_mv	info:eu-repo/semantics/article
format	article
dc.identifier.none.fl_str_mv	https://hdl.handle.net/20.500.12412/6894
url	https://hdl.handle.net/20.500.12412/6894
dc.language.none.fl_str_mv	Español
language_invalid_str_mv	Español
dc.relation.none.fl_str_mv	This work was supported by grant CNS2023-144725 funded by MICIU/AEI/10.13039/501100011033 and, by “European Union NextGenerationEU/PRTR” and grant from the Fondo de Investigación Sanitaria (FIS; PI18/01216, PI20/00326 and PI21/00357) which are co-funded by Fondos Europeos para el Desarrollo Regional (FEDER) “A way to make Europe”; the Instituto de Salud Carlos III (FI19/00298 to VGR; CD19/00143 toÁB-R, CM19/00051 to IO-M and CP19/00146 to AR); the Consejerı́a de Transformación Económica, Industria, Conocimiento y Universidades (DOC_01646 to MP-B) and the Consejerı́a de Salud y Familias of Junta de Andalucı́a through the “Nicolás Monardes” (RC-0006–2021 to YP). The HIV BioBank is supported by Instituto de Salud Carlos III (PT20/00138) and Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN (CB22/01/00041). CoRIS cohort is supported by CIBER - Consorcio Centro de Investigación Biomédica en Red (CB21/13/00091), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea—NextGenerationEU. AR and JP are also supported by CIBER-INF (CB21/13/00020). The funders had no role in the study design, data collection and interpretation, or the decision to submit the work for publication.
dc.rights.none.fl_str_mv	http://creativecommons.org/licenses/by-nc-nd/4.0/ info:eu-repo/semantics/openAccess
rights_invalid_str_mv	http://creativecommons.org/licenses/by-nc-nd/4.0/
eu_rights_str_mv	openAccess
dc.source.none.fl_str_mv	reponame:Brújula instname:Universidad Loyola Andalucía
instname_str	Universidad Loyola Andalucía
reponame_str	Brújula
collection	Brújula
repository.name.fl_str_mv
repository.mail.fl_str_mv
_version_	1869407372641828864
spelling	Unveiling altered CD8 T-cell metabolism and homeostatic proliferation behind a low CD4/CD8 ratio in ART-suppressed HIV individuals with normal CD4 recoveryDescubriendo alteraciones en el metabolismo de las células T CD8 y la proliferación homeostática detrás de una baja relación CD4/CD8 en individuos con VIH suprimidos por TAR con recuperación normal de CD4Garrido-Rodríguez, VanesaBulnes-Ramos, ÁngelOlivas-Martínez, IsraelPozo-Balado, Maria del MarTejerina-Picado, FranciscoGutiérrez, FélixMarco-Sánchez, CristinaTiraboschi, Juan ManuelCastillo-Navarro, AntoniaBernal, EnriqueGarcía-Guerrero, Maria C.Puertas, Maria C.Peraire, JoaquimRull, AnnaMartinez-Picado, JavierPacheco, Yolanda MaríaHIV-infectionCD4/CD8 ratioNadir-CD4 T cellImmunometabolismViral reservoirThymic outputBackground: People living with chronic HIV (PLWH) show immune dysfunction, despite viral suppression and normal CD4 recovery, particularly those with low CD4/CD8 ratios. Subjacent cellular alterations of such a reliable marker of clinical progression remain elusive. Methods: Categorization by CD4/CD8 ratio after three year of therapy (R < 0.8/R > 1.2, n = 28/n = 24) and post-hoc reclassification by nadir-CD4 (N ≤ 350/N > 350) were performed in PLWH achieving viral suppression and CD4 ≥ 500. CD4 T cell–associated viral reservoir, as well as metabolism-related gene expression, glucose uptake ability, relative telomere length (RTL), and thymic output for CD4 and CD8 T cells, were determined. Results: Patients with a CD4/CD8 ratio < 0.8 exhibited reduced CD8 T-cell glucose uptake ability after stimulation (p = 0.007) and trends to shorter RTL (p = 0.093) and to larger CD4-associated viral reservoir (p = 0.068) than R > 1.2. Differently, patients with nadir ≤350 exhibited altered CD4 and CD8 T-cell expression of metabolism-related genes, although no differences in glucose uptake ability, and shorter RTL in both cell subsets, but similar viral reservoir to patients with nadir >350. Remarkably, viral reservoir and both CD4 and CD8 thymic output showed inverse associations (r = −0.623, p = 0.01 and r = −0.661, p = 0.038, respectively). Conclusion: A low CD4/CD8 ratio in chronic PLWH stands on a larger viral reservoir in CD4 T cells and metabolic alterations in CD8 T cells, probably related to its exhaustion and compromised effector functionality, and thymic output could contribute to such alterations. Patients with lower nadir-CD4 showed a resting-like CD4 phenotype and a metabolically active CD8 subset, without further viral reservoir extension. Persistence of low CD4/CD8 ratio and low nadir-CD4 counts seems to rely on different immune damage.Antecedentes: Las personas que viven con el VIH crónico presentan disfunción inmunitaria, a pesar de la supresión viral y la recuperación normal de CD4, en particular aquellas con bajos cocientes CD4/CD8. Las alteraciones celulares subyacentes de este marcador fiable de progresión clínica aún no se comprenden del todo. Métodos: Se realizó una categorización por cociente CD4/CD8 después de tres años de terapia (R < 0,8/R > 1,2, n = 28/ n = 24) y una reclasificación post hoc por nadir-CD4 ( N ≤ 350/ N > 350) en personas con VIH que lograron la supresión viral y CD4 ≥ 500. Se determinó el reservorio viral asociado a las células T CD4, así como la expresión génica relacionada con el metabolismo, la capacidad de captación de glucosa, la longitud relativa de los telómeros (LRT) y la producción tímica para las células T CD4 y CD8. Resultados: Los pacientes con una relación CD4/CD8 < 0,8 mostraron una menor capacidad de captación de glucosa por las células T CD8 tras la estimulación ( p = 0,007) y una tendencia a una menor longitud tímica relativa ( p = 0,093) y a un mayor reservorio viral asociado a CD4 ( p = 0,068) que aquellos con una relación CD4/CD8 > 1,2. Por otro lado, los pacientes con un nadir ≤ 350 presentaron una expresión alterada de genes relacionados con el metabolismo en las células T CD4 y CD8, aunque sin diferencias en la capacidad de captación de glucosa, y una menor longitud tímica relativa en ambos subconjuntos celulares, pero un reservorio viral similar al de los pacientes con un nadir > 350. Cabe destacar que el reservorio viral y la producción tímica de CD4 y CD8 mostraron correlaciones inversas ( r = −0,623, p = 0,01 y r = −0,661, p = 0,038, respectivamente). Conclusión: Una baja proporción CD4/CD8 en personas con VIH crónico se asocia a un mayor reservorio viral en las células T CD4 y a alteraciones metabólicas en las células T CD8, probablemente relacionadas con su agotamiento y la disminución de su función efectora. La actividad tímica podría contribuir a dichas alteraciones. Los pacientes con un nadir de CD4 bajo mostraron un fenotipo de CD4 en reposo y una subpoblación de CD8 metabólicamente activa, sin mayor extensión del reservorio viral. La persistencia de una baja proporción CD4/CD8 y un recuento bajo de CD4 en el nadir parecen depender de diferentes tipos de daño inmunológico.2025info:eu-repo/semantics/articlehttps://hdl.handle.net/20.500.12412/6894reponame:Brújulainstname:Universidad Loyola AndalucíaEspañolThis work was supported by grant CNS2023-144725 funded by MICIU/AEI/10.13039/501100011033 and, by “European Union NextGenerationEU/PRTR” and grant from the Fondo de Investigación Sanitaria (FIS; PI18/01216, PI20/00326 and PI21/00357) which are co-funded by Fondos Europeos para el Desarrollo Regional (FEDER) “A way to make Europe”; the Instituto de Salud Carlos III (FI19/00298 to VGR; CD19/00143 toÁB-R, CM19/00051 to IO-M and CP19/00146 to AR); the Consejerı́a de Transformación Económica, Industria, Conocimiento y Universidades (DOC_01646 to MP-B) and the Consejerı́a de Salud y Familias of Junta de Andalucı́a through the “Nicolás Monardes” (RC-0006–2021 to YP). The HIV BioBank is supported by Instituto de Salud Carlos III (PT20/00138) and Networking Research Center on Bioengineering, Biomaterials and Nanomedicine, CIBER-BBN (CB22/01/00041). CoRIS cohort is supported by CIBER - Consorcio Centro de Investigación Biomédica en Red (CB21/13/00091), Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación and Unión Europea—NextGenerationEU. AR and JP are also supported by CIBER-INF (CB21/13/00020). The funders had no role in the study design, data collection and interpretation, or the decision to submit the work for publication.http://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccessoai:repositorio.uloyola.es:20.500.12412/68942026-06-24T12:48:37Z
score	15.811543

Unveiling altered CD8 T-cell metabolism and homeostatic proliferation behind a low CD4/CD8 ratio in ART-suppressed HIV individuals with normal CD4 recovery

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