La implicación de las quimiocinas y las adipoquinas en la respuesta inmune discordante en la infección por el VIH

Des de l'inici del tractament antiretroviral, la mortalitat i la morbilitat pel VIH han disminuït dràsticament, però tot i així, un percentatge no menyspreable de persones que viuen amb VIH (PLHIV) no aconsegueixen recuperar els recomptes de T-CD4+ malgrat una correcta supressió virològica. Els mecanismes implicats en aquesta pobra recuperació immune són múltiples i complexos, i fins ara no han pogut ser dilucidats completament. L'objectiu d'aquesta tesi és determinar la implicació de les quimiocines i les adipoquines a la resposta immune discordant. Tant les quimiocines com les adipoquines són citoquines que juguen un paper essencial en la resposta immune, i la seva secreció i producció es veu alterada en la infecció pel VIH, cosa que té repercussió en la recuperació immune. Per estudiar l'efecte d'aquestes citocines a la pobra resposta immune al VIH es van dur a terme dos estudis dels quals han derivat dues publicacions científiques. En tots dos treballs es van reclutar pacients amb VIH que es van classificar en funció dels seus recomptes de T-CD4+ basals, i posteriorment en funció del grau de recuperació immune. Es van analitzar les concentracions de quimiocines, les seves variants genètiques i adipoquines tant a nivell basal com durant el seguiment. Els resultats obtinguts conclouen que les quimiocines i les adipoquines estan implicades en la recuperació immune i que poden servir com a marcadors pronòstics d'una resposta immune discordant.Desde el inicio del tratamiento antiretroviral, la mortalidad y morbilidad por VIH han disminuido drásticamente, pero aún así, un porcentaje no desdeñable de personas que viven con VIH (PLHIV) no consiguen recuperar los recuentos de T-CD4+ a pesar de una correcta supresión virológica. Los mecanismos implicados en esta pobre recuperación inmune, son múltiples y complejos, y hasta ahora no han podido ser dilucidados completamente. El objetivo de esta tesis es determinar la implicación de las quimiocinas y las adipoquinas en la respuesta inmune discordante. Tanto las quimiocinas como las adipoquinas son citoquinas que juegan un papel esencial en la respuesta inmune, y su secreción y producción se ve alterada en la infección por el VIH, lo que tiene repercusión en la recuperación inmune. Para estudiar el efecto de estas citoquinas en la pobre respuesta inmune en el VIH se llevaron a cabo dos estudios de los cuales han derivado sendas publicaciones científicas. En ambos trabajos se reclutaron pacientes con VIH que se clasificaron en función de sus recuentos de T-CD4+ basales, y posteriormente en función de su grado de recuperación inmune. Se analizaron las concentraciones de quimiocinas, sus variantes genéticas y adipoquinas tanto a nivel basal como durante el seguimiento. Los resultados obtenidos concluyen que las quimiocinas y las adipoquinas están implicadas en la recuperación inmune y que pueden servir como marcadores pronósticos de una respuesta inmune discordante.Since the start of antiretroviral treatment, mortality and morbidity due to HIV have drastically decreased, but even so, a non-negligible percentage of people living with HIV (PLHIV) do not manage to recover their T-CD4+ counts despite correct virological suppression. The mechanisms involved in this poor immune recovery are multiple and complex, and until now they have not been fully elucidated. The objective of this thesis is to determine the involvement of chemokines and adipokines in the discordant immune response. Both chemokines and adipokines are cytokines that play an essential role in the immune response, and their secretion and production is altered in HIV infection, which has repercussions on immune recovery. To study the effect of these cytokines on the poor immune response in HIV, two studies were carried out, which have resulted in two scientific publications. In both studies, patients with HIV were recruited and were classified according to their baseline T-CD4+ counts, and later according to their degree of immune recovery. Chemokine concentrations, their genetic variants, and adipokines were analyzed both at baseline and during follow-up. The results obtained conclude that chemokines and adipokines are involved in immune recovery and that they can serve as prognostic markers of a discordant immune response

High circulating SDF-1and MCP-1 levels and genetic variations in CXCL12, CCL2 and CCR5: Prognostic signature of immune recovery status in treated HIV-positive patients

Background: The underlying mechanisms of incomplete immune reconstitution in treated HIV-positive patients are very complex and may be multifactorial, but perturbation of chemokine secretion could play a key role in CD4+ T-cell turnover. Methods: We evaluated the circulating baseline and 48-week follow-up concentrations of SDF-1/CXCL12, fractalkine/CX3CL1, MCP-1/CCL2, MIP-α/CCL3, MIP-β/CCL4 and RANTES/CCL5, and we estimated their association with CXCL12, CX3CR1, CCR2, CCL5 and CCR5 single nucleotide polymorphisms (SNPs) to investigate multiple chemokine-chemokine receptor signatures associated with immune dysregulation preceding poor immune recovery. Findings: The circulating concentrations and gene expression patterns of SDF-1/CXCL12 (CXCL12 rs1801157) and MCP-1/CCL2 (CCR2 rs1799864_814) were associated with immune recovery status. CCR2 rs1799864_814 and CCR5 rs333_814 (Δ32) determine the baseline plasma RANTES and MIP-α concentrations, respectively, in participants with poor immune response. Interpretation: SDF-1/CXCL12 and MCP-1/CCL2 could be considered prognostic markers of immune failure despite suppressive antiretroviral therapy. The strong linkage disequilibrium (LD) between CCR2 rs1799864_814 and CCR5 rs1800024 indicated that the alleles of each gene are inherited together more often than would be expected by chance. Funding: This work was supported by Fondo de Investigacion Sanitaria and SPANISH AIDS Research Network (ISCIII-FEDER); AGAUR and Gilead Fellowship. FV and YMP are supported by grants from the Programa de Intensificación (ISCIII) and Servicio Andaluz de Salud, respectively. JVG,EY and LR are supported by the Instituto de Salud Carlos III (ISCIII). AR is supported by Departament de Salut, Generalitat de Catalunya and by the Instituto de Salud Carlos III (ISCIII)

High circulating SDF-1and MCP-1 levels and genetic variations in CXCL12, CCL2 and CCR5 : Prognostic signature of immune recovery status in treated HIV-positive patients

The underlying mechanisms of incomplete immune reconstitution in treated HIV-positive patients are very complex and may be multifactorial, but perturbation of chemokine secretion could play a key role in CD4 T-cell turnover. We evaluated the circulating baseline and 48-week follow-up concentrations of SDF-1/CXCL12, fractalkine/CX3CL1, MCP-1/CCL2, MIP-α/CCL3, MIP-β/CCL4 and RANTES/CCL5, and we estimated their association with CXCL12, CX3CR1, CCR2, CCL5 and CCR5 single nucleotide polymorphisms (SNPs) to investigate multiple chemokine-chemokine receptor signatures associated with immune dysregulation preceding poor immune recovery. The circulating concentrations and gene expression patterns of SDF-1/CXCL12 (CXCL12 rs1801157) and MCP-1/CCL2 (CCR2 rs1799864_814) were associated with immune recovery status. CCR2 rs1799864_814 and CCR5 rs333_814 (Δ32) determine the baseline plasma RANTES and MIP-α concentrations, respectively, in participants with poor immune response. SDF-1/CXCL12 and MCP-1/CCL2 could be considered prognostic markers of immune failure despite suppressive antiretroviral therapy. The strong linkage disequilibrium (LD) between CCR2 rs1799864_814 and CCR5 rs1800024 indicated that the alleles of each gene are inherited together more often than would be expected by chance. This work was supported by Fondo de Investigacion Sanitaria and SPANISH AIDS Research Network (ISCIII-FEDER); AGAUR and Gilead Fellowship. FV and YMP are supported by grants from the Programa de Intensificación (ISCIII) and Servicio Andaluz de Salud, respectively. JVG,EY and LR are supported by the Instituto de Salud Carlos III (ISCIII). AR is supported by Departament de Salut, Generalitat de Catalunya and by the Instituto de Salud Carlos III (ISCIII)

Elevated α-Ketoglutaric Acid Concentrations and a Lipid-Balanced Signature Are the Key Factors in Long-Term HIV Control

Long-term elite controllers (LTECs) are a fascinating small subset of HIV individuals with viral and immunological HIV control in the long term that have been designated as models of an HIV functional cure. However, data on the LTEC phenotype are still scarce, and hence, the metabolomics and lipidomics signatures in the LTEC-extreme phenotype, LTECs with more than 10 years of viral and immunological HIV control, could be pivotal to finding the keys for functional HIV remission. Metabolomics and lipidomics analyses were performed using high-resolution mass spectrometry (ultra-high-performance liquid chromatography-electrospray ionization-quadrupole time of flight [UHPLC-(ESI) qTOF] in plasma samples of 13 patients defined as LTEC-extreme, a group of 20 LTECs that lost viral and/or immunological control during the follow-up study (LTEC-losing) and 9 EC patients with short-term viral and immunological control (less than 5 years; no-LTEC patients). Long-term viral and immunological HIV-1 control was found to be strongly associated with elevated tricarboxylic acid (TCA) cycle function. Interestingly, of the nine metabolites identified in the TCA cycle, α-ketoglutaric acid (p = 0.004), a metabolite implicated in the activation of the mTOR complex, a modulator of HIV latency and regulator of several biological processes, was found to be a key metabolite in the persistent control. On the other hand, a lipidomics panel combining 45 lipid species showed an optimal percentage of separation and an ability to differentiate LTEC-extreme from LTEC-losing, revealing that an elevated lipidomics plasma profile could be a predictive factor for the reignition of viral replication in LTEC individuals.This work was supported by the Fondo de Investigación Sanitaria [PI13/0796, PI16/00503, PI16/0684, PI18/1532, PI19/00004, PI19/01127, PI19/01337 PI16/001769, PI19/00973, and PI20/00326]-ISCIII-FEDER (co-funded by the European Regional Development Fund/European Social Fund; “A way to make Europe”/”Investing in your future”); Programa de Suport als Grups de Recerca AGAUR (2017SGR948); Gilead Fellowship Program GLD14/293; The SPANISH AIDS Research Network [RD16/0002/0001, RD16/0002/0002, RD16/0025/0006, RD16/0025/0013, and RD16/0025/0020]-ISCIII-FEDER (Spain); and the Centro de Investigación Biomédica en Red de Enfermedades Infecciosas-ISCIII [CB21/13/00015, CB21/13/00020, and CB21/13/00044], Madrid, Spain. JM is supported by the Universitat Rovira I Virgili under grant agreement “2019PMF-PIPF-18,” through the call “Martí Franquès Research Fellowship Programme.” NR is a Miguel Servet researcher from the ISCIII [CPII19/00025]. EY is supported by the Instituto de Salud Carlos III (ISCIII) under grant agreement “FI20/0011800” through the program “Contratos Predoctorales de Formación en Investigación en Salud.” ER-M was supported by the Spanish National Research Council (CSIC). FV is supported by grants from the Programa de Intensificación de Investigadores (INT20/00031)-ISCIII and by “Premi a la Trajectòria Investigadora als Hospitals de l’ICS 2018.” AR is supported by IISPV through the project “2019/IISPV/05” (Boosting Young Talent), by GeSIDA through the “III Premio para Jóvenes Investigadores 2019,” and by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CP19/00146” through the Miguel Servet Program.S

Adipokines as New Biomarkers of Immune Recovery: Apelin Receptor, RBP4 and ZAG Are Related to CD4+ T-Cell Reconstitution in PLHIV on Suppressive Antiretroviral Therapy

A significant proportion of people living with HIV (PLHIV) who successfully achieve virological suppression fail to recover CD4+ T-cell counts. Since adipose tissue has been discovered as a key immune organ, this study aimed to assess the role of adipokines in the HIV immunodiscordant response. This is a multicenter prospective study including 221 PLHIV starting the first antiretroviral therapy (ART) and classified according to baseline CD4+ T-cell counts/µL (controls > 200 cells/µL and cases ≤ 200 cells/µL). Immune failure recovery was considered when cases did not reach more than 250 CD4+ T cells/µL at 144 weeks (immunological nonresponders, INR). Circulating adipokine concentrations were longitudinally measured using enzyme-linked immunosorbent assays. At baseline, apelin receptor (APLNR) and zinc-alpha-2-glycoprotein (ZAG) concentrations were significantly lower in INRs than in immunological responders (p = 0.043 and p = 0.034), and they remained lower during all ART follow-up visits (p = 0.044 and p = 0.028 for APLNR, p = 0.038 and p = 0.010 for ZAG, at 48 and 144 weeks, respectively). ZAG levels positively correlated with retinol-binding protein 4 (RBP4) levels (p < 0.01), and low circulating RBP4 concentrations were related to a low CD4+ T-cell gain (p = 0.018 and p = 0.039 at 48 and 144 weeks, respectively). Multiple regression adjusted for clinical variables and adipokine concentrations confirmed both low APLNR and RBP4 as independent predictors for CD4+ T cells at 144 weeks (p < 0.001). In conclusion, low APLNR and RBP4 concentrations were associated with poor immune recovery in treated PLHIV and could be considered predictive biomarkers of a discordant immunological response

Adipokines as New Biomarkers of Immune Recovery: Apelin Receptor, RBP4 and ZAG Are Related to CD4+ T-Cell Reconstitution in PLHIV on Suppressive Antiretroviral Therapy.

A significant proportion of people living with HIV (PLHIV) who successfully achieve virological suppression fail to recover CD4+ T-cell counts. Since adipose tissue has been discovered as a key immune organ, this study aimed to assess the role of adipokines in the HIV immunodiscordant response. This is a multicenter prospective study including 221 PLHIV starting the first antiretroviral therapy (ART) and classified according to baseline CD4+ T-cell counts/µL (controls > 200 cells/µL and cases ≤ 200 cells/µL). Immune failure recovery was considered when cases did not reach more than 250 CD4+ T cells/µL at 144 weeks (immunological nonresponders, INR). Circulating adipokine concentrations were longitudinally measured using enzyme-linked immunosorbent assays. At baseline, apelin receptor (APLNR) and zinc-alpha-2-glycoprotein (ZAG) concentrations were significantly lower in INRs than in immunological responders (p = 0.043 and p = 0.034), and they remained lower during all ART follow-up visits (p = 0.044 and p = 0.028 for APLNR, p = 0.038 and p = 0.010 for ZAG, at 48 and 144 weeks, respectively). ZAG levels positively correlated with retinol-binding protein 4 (RBP4) levels (p 200 cells/µL and cases ≤ 200 cells/µL). Immune failure recovery was considered when cases did not reach more than 250 CD4+ T cells/µL at 144 weeks (immunological nonresponders, INR). Circulating adipokine concentrations were longitudinally measured using enzyme-linked immunosorbent assays. At baseline, apelin receptor (APLNR) and zinc-alpha-2-glycoprotein (ZAG) concentrations were significantly lower in INRs than in immunological responders (p = 0.043 and p = 0.034), and they remained lower during all ART follow-up visits (p = 0.044 and p = 0.028 for APLNR, p = 0.038 and p = 0.010 for ZAG, at 48 and 144 weeks, respectively). ZAG levels positively correlated with retinol-binding protein 4 (RBP4) levels (

Fetuin-A, inter-α-trypsin inhibitor, glutamic acid and ChoE (18:0) are key biomarkers in a panel distinguishing mild from critical coronavirus disease 2019 outcomes

The mechanistic pathways leading to immune dysregulation and complications driven by uncontrolled severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection remain major challenges.1, 2 Hence, a detailed analysis of the proteome, metabolome and lipidome profile of coronavirus disease 2019 (COVID-19) patients showing different severity grades might shed light on the disease pathophysiology and unveil new predictive biomarkers to promptly ascertain patient's outcomes. Our COVID-19 study cohort included 273 SARS-CoV-2 infected individuals recruited during the first wave (March–April 2020) in three different hospitals and grouped by the disease severity following the medical inclusion criteria3 in mild, severe or critical (Figure 1A), from whom demographic, preexisting clinical conditions and COVID-19 treatments are summarized in Table S1. The greatest significant differences were observed between mild and critically ill patients. These findings indicated that older individuals with comorbidities such as hypertension, obesity, diabetes and cardiovascular disorders, mostly presenting dyspnea (Figure 1B), may be at higher risk of suffering from severe respiratory distress with subsequent oxygen and drug requirements and, eventually, died. Similarly, the serum biochemical composition analysis revealed a well-differentiated blood pattern previously defined for critically ill patients (Figure S1).This work has been developed in the framework of the COVIDOMICS’ project supported by Direcció General de Recerca i Innovació en Salut (DGRIS), Departament de Salut, Generalitat de Catalunya (PoC-6-17 and PoC1-5). The research has also been funded by the Programa de Suport als Grups de Recerca AGAUR (2017SGR948), the SPANISH AIDS Research Network [RD16/0025/0006, RD16/0025/0007 and RD16/0025/0020]-ISCIII-FEDER (Spain), the Centro de Investigación Biomédica en Red de Enfermedades Infecciosas-ISCIII [CB21/13/00020], Madrid, Spain and Consejeria de Transformacion Economica, Industria, Conocimiento y Universidades Junta de Andalucía (research Project CV20-85418). Elena Yeregui was supported by the Instituto de Salud Carlos III (ISCIII) under grant agreement “FI20/00118″ through the programme “Contratos Predoctorales de Formación en Investigación en Salud”. Laia Revertéwas supported by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CD20/00105″ through the programme “Contratos Sara Borrell”. Francesc Vidal was supported by grants from the Programa de Intensificación de Investigadores (INT20/00031)-ISCIII and by “Premi a la Trajectòria Investigadora dels Hospitals de l’ICS 2018″. Anna Rull was supported by a grant from IISPV through the project “2019/IISPV/05″ (Boosting Young Talent), by GeSIDA through the “III Premio para Jóvenes Investigadores 2019″ and by the Instituto de Salud Carlos III (ISCIII) under grant agreement “CP19/00146″ through the Miguel Servet Program. Maria José Buzón was supported by the Miguel Servet Program (CP17/00179). Ezequiel Ruiz- Mateos was supported by the Spanish Research Council (CSIC). Alicia Gutiérrez-Valencia was supported by the Instituto de Salud Carlos III, cofinanced by the European Development Regional Fund (“A way to achieve Europe”), Subprograma Miguel Servet (grant CP19/00159). This project was also funded by a donation from the city Council of Perafort (to Teresa Auguet).Peer reviewe

Discovering HIV related information by means of association rules and machine learning

Acquired immunodeficiency syndrome (AIDS) is still one of the main health problems worldwide. It is therefore essential to keep making progress in improving the prognosis and quality of life of affected patients. One way to advance along this pathway is to uncover connections between other disorders associated with HIV/AIDS-so that they can be anticipated and possibly mitigated. We propose to achieve this by using Association Rules (ARs). They allow us to represent the dependencies between a number of diseases and other specific diseases. However, classical techniques systematically generate every AR meeting some minimal conditions on data frequency, hence generating a vast amount of uninteresting ARs, which need to be filtered out. The lack of manually annotated ARs has favored unsupervised filtering, even though they produce limited results. In this paper, we propose a semi-supervised system, able to identify relevant ARs among HIV-related diseases with a minimal amount of annotated training data. Our system has been able to extract a good number of relationships between HIV-related diseases that have been previously detected in the literature but are scattered and are often little known. Furthermore, a number of plausible new relationships have shown up which deserve further investigation by qualified medical experts

COVID-19 in hospitalized HIV-positive and HIV-negative patients : A matched study

CatedresObjectives: We compared the characteristics and clinical outcomes of hospitalized individuals with COVID-19 with [people with HIV (PWH)] and without (non-PWH) HIV co-infection in Spain during the first wave of the pandemic. Methods: This was a retrospective matched cohort study. People with HIV were identified by reviewing clinical records and laboratory registries of 10 922 patients in active-follow-up within the Spanish HIV Research Network (CoRIS) up to 30 June 2020. Each hospitalized PWH was matched with five non-PWH of the same age and sex randomly selected from COVID-19@Spain, a multicentre cohort of 4035 patients hospitalized with confirmed COVID-19. The main outcome was all-cause in-hospital mortality. Results: Forty-five PWH with PCR-confirmed COVID-19 were identified in CoRIS, 21 of whom were hospitalized. A total of 105 age/sex-matched controls were selected from the COVID-19@Spain cohort. The median age in both groups was 53 (Q1-Q3, 46-56) years, and 90.5% were men. In PWH, 19.1% were injecting drug users, 95.2% were on antiretroviral therapy, 94.4% had HIV-RNA < 50 copies/mL, and the median (Q1-Q3) CD4 count was 595 (349-798) cells/μL. No statistically significant differences were found between PWH and non-PWH in number of comorbidities, presenting signs and symptoms, laboratory parameters, radiology findings and severity scores on admission. Corticosteroids were administered to 33.3% and 27.4% of PWH and non-PWH, respectively (P = 0.580). Deaths during admission were documented in two (9.5%) PWH and 12 (11.4%) non-PWH (P = 0.800). Conclusions: Our findings suggest that well-controlled HIV infection does not modify the clinical presentation or worsen clinical outcomes of COVID-19 hospitalization