Publications by authors named "Ariadna Torrella"

10 Publications

  • Page 1 of 1

Peripheral and lung resident memory T cell responses against SARS-CoV-2.

Nat Commun 2021 05 21;12(1):3010. Epub 2021 May 21.

Infectious Diseases Department, Vall d'Hebron Institut de Recerca (VHIR), Vall d'Hebron Hospital Universitari, Vall d'Hebron Barcelona Hospital Campus, Barcelona, Spain.

Resident memory T cells (T) positioned within the respiratory tract are probably required to limit SARS-CoV-2 spread and COVID-19. Importantly, T are mostly non-recirculating, which reduces the window of opportunity to examine these cells in the blood as they move to the lung parenchyma. Here, we identify circulating virus-specific T cell responses during acute infection with functional, migratory and apoptotic patterns modulated by viral proteins and associated with clinical outcome. Disease severity is associated predominantly with IFNγ and IL-4 responses, increased responses against S peptides and apoptosis, whereas non-hospitalized patients have increased IL-12p70 levels, degranulation in response to N peptides and SARS-CoV-2-specific CCR7 T cells secreting IL-10. In convalescent patients, lung-T are frequently detected even 10 months after initial infection, in which contemporaneous blood does not reflect tissue-resident profiles. Our study highlights a balanced anti-inflammatory antiviral response associated with a better outcome and persisting T cells as important for future protection against SARS-CoV-2 infection.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-021-23333-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140108PMC
May 2021

Lipidomics Reveals Reduced Inflammatory Lipid Species and Storage Lipids after Switching from EFV/FTC/TDF to RPV/FTC/TDF: A Randomized Open-Label Trial.

J Clin Med 2020 Apr 25;9(5). Epub 2020 Apr 25.

Internal Medicine Department. Complexo Hospitalario Universitario de Vigo; IIS Galicia Sur, 36312 Vigo, Spain.

HIV and antiretroviral therapy affect lipid metabolism. Lipidomics quantifies several individual species that are overlooked using conventional biochemical analyses, outperforming traditional risk equations. We aimed to compare the plasma lipidomic profile of HIV patients taking efavirenz (EFV) or rilpivirine (RPV). Patients ≥ 18 years old on EFV co-formulated with emtricitabine and tenofovir disoproxil fumarate (FTC/TDF) with HIV-RNA < 50 copies/mL for ≥6 months were randomized to continue EFV/FTC/TDF (n = 14) or switch to RPV/FTC/TDF (n =15). Lipidomic analyses conducted by mass spectrometry (MS) were performed at baseline and after 12 and 24 weeks. OWLiver Care and OWLiver tests were performed to estimate the presence of fatty liver disease (NAFLD). No significant differences (83% male, median age 44 years, 6 years receiving EFV/FTC/TDF, CD4 count 740 cells/mm, TC 207 [57 HDL-C/133 LDL-C] mg/dL, TG 117 mg/dL) were observed between the groups at baseline. Significant reductions in plasma lipids and lipoproteins but increased circulating bilirubin concentrations were observed in patients who switched to RPV/FTC/TDF. Patients on RPV/FTC/TDF showed a decrease in the global amount of storage lipids (-0.137 log [fold-change] EFV vs. 0.059 log [fold-change] RPV) but an increase in lysophosphatidylcholines (LPCs) and total steroids. Compared with EFV, RPV increased metabolites with anti-inflammatory properties and reduced the repository of specific lipotoxic lipids.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jcm9051246DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288166PMC
April 2020

Latency reversal agents affect differently the latent reservoir present in distinct CD4+ T subpopulations.

PLoS Pathog 2019 08 19;15(8):e1007991. Epub 2019 Aug 19.

Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.

Latency reversal agents (LRAs) have proven to induce HIV-1 transcription in vivo but are ineffective at decreasing the size of the latent reservoir in antiretroviral treated patients. The capacity of the LRAs to perturb the viral reservoir present in distinct subpopulations of cells is currently unknown. Here, using a new RNA FISH/flow ex vivo viral reactivation assay, we performed a comprehensive assessment of the viral reactivation capacity of different families of LRAs, and their combinations, in different CD4+ T cell subsets. We observed that a median of 16.28% of the whole HIV-reservoir induced HIV-1 transcripts after viral reactivation, but only 10.10% of these HIV-1 RNA+ cells produced the viral protein p24. Moreover, none of the LRAs were powerful enough to reactivate HIV-1 transcription in all CD4+ T cell subpopulations. For instance, the combination of Romidepsin and Ingenol was identified as the best combination of drugs at increasing the proportion of HIV-1 RNA+ cells, in most, but not all, CD4+ T cell subsets. Importantly, memory stem cells were identified as highly resistant to HIV-1 reactivation, and only the combination of Panobinostat and Bryostatin-1 significantly increased the number of cells transcribing HIV within this subset. Overall, our results validate the use of the RNA FISH/flow technique to assess the potency of LRAs among different CD4+ T cell subsets, manifest the intrinsic differences between cells that encompass the latent HIV reservoir, and highlight the difficulty to significantly impact the latent infection with the currently available drugs. Thus, our results have important implications for the rational design of therapies aimed at reversing HIV latency from diverse cellular reservoirs.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1371/journal.ppat.1007991DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6715238PMC
August 2019

Expression of CD20 after viral reactivation renders HIV-reservoir cells susceptible to Rituximab.

Nat Commun 2019 08 16;10(1):3705. Epub 2019 Aug 16.

Infectious Disease Department, Hospital Universitari Vall d'Hebrón, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain.

The identification of exclusive markers to target HIV-reservoir cells will represent a significant advance in the search for therapies to cure HIV. Here, we identify the B lymphocyte antigen CD20 as a marker for HIV-infected cells in vitro and in vivo. The CD20 molecule is dimly expressed in a subpopulation of CD4-positive (CD4) T lymphocytes from blood, with high levels of cell activation and heterogeneous memory phenotypes. In lymph node samples from infected patients, CD20 is present in productively HIV-infected cells, and ex vivo viral infection selectively upregulates the expression of CD20 during early infection. In samples from patients on antiretroviral therapy (ART) this subpopulation is significantly enriched in HIV transcripts, and the anti-CD20 monoclonal antibody Rituximab induces cell killing, which reduces the pool of HIV-expressing cells when combined with latency reversal agents. We provide a tool for targeting this active HIV-reservoir after viral reactivation in patients while on ART.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41467-019-11556-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6697690PMC
August 2019

Switching From a Protease Inhibitor-based Regimen to a Dolutegravir-based Regimen: A Randomized Clinical Trial to Determine the Effect on Peripheral Blood and Ileum Biopsies From Antiretroviral Therapy-suppressed Human Immunodeficiency Virus-infected Individuals.

Clin Infect Dis 2019 09;69(8):1320-1328

AIDS Research Institute IrsiCaixa, Badalona.

Background: Optimization of combination antiretroviral therapy (cART) can impact the human immunodeficiency virus (HIV) reservoir. We evaluated the effect on the HIV reservoir in peripheral blood and ileum biopsies in patients switching from boosted protease inhibitor (PI/r)-based therapy to dolutegravir (DTG)-based therapy.

Methods: Impact of Integrase-inhibitor DOlutegravir On the viral Reservoir (INDOOR) is a phase 4 open-label clinical trial that randomly included 42 HIV type 1-infected individuals on effective cART: 20 who switched from PI/r-based to DTG-based cART (switch group), and 22 who remained in PI/r-based regimens (control group). We analyzed blood and ileum biopsies to quantify episomal, total, and integrated HIV DNA, cell-associated HIV RNA, residual plasma viremia, T-cell subsets, cell activation, and inflammation markers.

Results: There were no related adverse events or treatment discontinuations due to drug intolerance. The HIV reservoir was consistently larger in ileal than in peripheral CD4+ T cells in both groups (P < .01). Residual viremia in plasma decreased in the switch group (P = .03). However, we did not observe significant longitudinal changes in low-level viral replication, total and integrated HIV reservoir, HIV transcription, T-cell maturation subsets, immunoactivation markers, inflammatory soluble proteins, or cellular markers of latently infected cells.

Conclusions: The INDOOR study is the first evaluation of changes in HIV reservoir size in ileum biopsies and in peripheral blood in individuals switched from PI/r- to DTG-based cART. Although this switch was safe and well tolerated, it had no impact on a large array of immunological and inflammatory markers or on HIV reservoir markers in peripheral or in ileal CD4+ T cells.

Clinical Trials Registration: EudraCT 2014-004331-39.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/cid/ciy1095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763634PMC
September 2019

Low nadir CD4+ T-cell counts predict gut dysbiosis in HIV-1 infection.

Mucosal Immunol 2019 01 31;12(1):232-246. Epub 2018 Aug 31.

irsiCaixa AIDS Research Institute, Ctra de Canyet s/n, Badalona, 08916, Catalonia, Spain.

Human immunodeficiency virus (HIV)-1 infection causes severe gut and systemic immune damage, but its effects on the gut microbiome remain unclear. Previous shotgun metagenomic studies in HIV-negative subjects linked low-microbial gene counts (LGC) to gut dysbiosis in diseases featuring intestinal inflammation. Using a similar approach in 156 subjects with different HIV-1 phenotypes, we found a strong, independent, dose-effect association between nadir CD4+ T-cell counts and LGC. As in other diseases involving intestinal inflammation, the gut microbiomes of subjects with LGC were enriched in gram-negative Bacteroides, acetogenic bacteria and Proteobacteria, which are able to metabolize reactive oxygen and nitrogen species; and were depleted in oxygen-sensitive methanogenic archaea and sulfate-reducing bacteria. Interestingly, subjects with LGC also showed increased butyrate levels in direct fecal measurements, consistent with enrichment in Roseburia intestinalis despite reductions in other butyrate producers. The microbiomes of subjects with LGC were also enriched in bacterial virulence factors, as well as in genes associated with beta-lactam, lincosamide, tetracycline, and macrolide resistance. Thus, low nadir CD4+ T-cell counts, rather than HIV-1 serostatus per se, predict the presence of gut dysbiosis in HIV-1 infected subjects. Such dysbiosis does not display obvious HIV-specific features; instead, it shares many similarities with other diseases featuring gut inflammation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41385-018-0083-7DOI Listing
January 2019

A Novel Single-Cell FISH-Flow Assay Identifies Effector Memory CD4 T cells as a Major Niche for HIV-1 Transcription in HIV-Infected Patients.

mBio 2017 07 11;8(4). Epub 2017 Jul 11.

Department of Infectious Diseases, Hospital Universitari Vall d'Hebrón, Institut de Recerca (VHIR), Universitat Autònoma de Barcelona, Barcelona, Spain

Cells that actively transcribe HIV-1 have been defined as the "active viral reservoir" in HIV-infected individuals. However, important technical limitations have precluded the characterization of this specific viral reservoir during both treated and untreated HIV-1 infections. Here, we used a novel single-cell RNA fluorescence hybridization-flow cytometry (FISH-flow) assay that requires only 15 million unfractionated peripheral blood mononuclear cells (PBMCs) to characterize the specific cell subpopulations that transcribe HIV RNA in different subsets of CD4 T cells. In samples from treated and untreated HIV-infected patients, effector memory CD4 T cells were the main cell population supporting HIV RNA transcription. The number of cells expressing HIV correlated with the plasma viral load, intracellular HIV RNA, and proviral DNA quantified by conventional methods and inversely correlated with the CD4 T cell count and the CD4/CD8 ratio. We also found that after infection of unstimulated PBMCs, HIV-infected T cells upregulated the expression of CD32. In addition, this new methodology detected increased numbers of primary cells expressing viral transcripts and proteins after viral reactivation with latency reversal agents. This RNA FISH-flow technique allows the identification of the specific cell subpopulations that support viral transcription in HIV-1-infected individuals and has the potential to provide important information on the mechanisms of viral pathogenesis, HIV persistence, and viral reactivation. Persons infected with HIV-1 contain several cellular viral reservoirs that preclude the complete eradication of the viral infection. Using a novel methodology, we identified effector memory CD4 T cells, immune cells preferentially located in inflamed tissues with potent activity against pathogens, as the main cells encompassing the transcriptionally active HIV-1 reservoir in patients on antiretroviral therapy. Importantly, the identification of such cells provides us with an important target for new therapies designed to target the hidden virus and thus to eliminate the virus from the human body. In addition, because of its ability to identify cells forming part of the viral reservoir, the assay used in this study represents an important new tool in the field of HIV pathogenesis and viral persistence.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/mBio.00876-17DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5513707PMC
July 2017

Acute leg ischaemia in an HIV-infected patient receiving antiretroviral treatment.

Antivir Ther 2017 22;22(1):89-90. Epub 2016 Aug 22.

Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

An HIV-infected patient treated with tenofovir disoproxil fumarate/emtricitabine/elvitegravir/cobicistat developed severe acute ischaemia of both legs during a migraine episode. After being interrogated he admitted taking an ergotamine-containing preparation. Ergotism due to interaction between ergotics and cobicistat was diagnosed. We describe the first reported case of this interaction.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3851/IMP3075DOI Listing
January 2018

Impact of low-level viraemia on virological failure in HIV-1-infected patients with stable antiretroviral treatment.

Antivir Ther 2016 12;21(4):345-52. Epub 2016 Jan 12.

Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Background: Low-level viraemia (LLV) occurs in 20-40% of patients achieving viral suppression with antiretroviral therapy (ART). The risk of virological failure (VF: confirmed HIV RNA >200 copies/ml) in these patients is still a matter of debate.

Methods: This is a prospective cohort study in HIV-infected adults attending the HIV clinic of a tertiary care hospital in Spain. Patients with HIV RNA <25 copies/ml and stable ART for at least 6 months presenting LLV (defined as HIV RNA between 25-1,000 copies/ml) from January 2011 to January 2013 were included and followed until VF or end of follow-up in June 2014.

Results: A total of 300 out of 1,733 (17.3%) patients with undetectable viraemia for 4.2 years showed LLV: 25-50 copies/ml in 167 (55.7%) patients, 51-200 copies/ml in 111 (37%) and 201-1,000 copies/ml in 22 (7.3%) cases. After a median follow-up of 2.6 years, 23 (7.7%) patients presented VF. No patient with a single or multiple unconfirmed LLV went on to develop VF. HIV RNA >200 copies/ml (HR 59.6; 95% CI 15.7, 227), ritonavir-boosted protease inhibtor (PI/r)-based dual therapy (HR 10.2; 95% CI 2.1, 49.8) and PI/r monotherapy (HR 7.9; 95% CI 1.4, 43.3) were associated with VF. Persistent LLV, defined as HIV RNA <200 copies/ml in at least three consecutive samples, for at least 12 weeks, was detected in 27 (1.6%) patients and 14 (51.9%) of those evolved to VF.

Conclusions: Nearly one-fifth of patients on suppressive ART showed LLV and 8% of them developed VF. HIV RNA >200 copies/ml was the strongest predictor of VF. Over half of patients with persistent viraemia <200 copies/ml showed VF.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3851/IMP3023DOI Listing
January 2018

Impact of an adherence program to antiretroviral treatment on virologic response in a cohort of multitreated and poorly adherent HIV-infected patients in Spain.

AIDS Patient Care STDS 2014 Oct 11;28(10):537-42. Epub 2014 Aug 11.

1 Infectious Diseases Department Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona , Barcelona, Spain .

Several studies have shown the importance of adherence to highly active antiretroviral therapy (HAART) in achieving HIV-1 suppression. However, most have focused on naïve patients and do not assess the impact of HAART on viral load (VL). Our aim was to evaluate the effectiveness of an adherence program in a cohort of multitreated and poorly adherent patients. We performed a cohort study of all adult HIV-1 infected patients with detectable VL who were treatment experienced and poorly adherent to HAART, included in an adherence program since its introduction in 2009 (n=136). The adherence program consisted of a multidisciplinary team with a nurse who specialized in behavioral intervention, counselling on substance abuse, and motivational interviewing, as well as a social worker responsible for referring patients to local healthcare centers. Effectiveness was evaluated as percentage of patients with VL <50 copies/mL at week 48 by modified intent-to-treat (mITT) analysis. Initially, 76.6% of the patients had an adherence <30% according to the Simplified Medication Adherence Questionnaire (SMAQ). At 48 weeks, 48.1% of the patients had VL <50 copies/mL, and the adherence was >90% in 71% of the patients. In multivariate analysis, a ratio of bottle refill per month >0.9 during the study [odds ratio (OR) 14.3; 95% confidence interval (CI) 4.08-50.08, p<0.001] and being on a b.i.d. regimen (OR 12.5; 95% CI 1.81-86.4, p=0.010) were associated with an undetectable VL. In conclusion, the adherence program was successful in almost half of the patients, despite their long treatment experience and prior poor adherence. This strategy may help to prevent disease progression and the risk of HIV transmission in these patients.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1089/apc.2014.0097DOI Listing
October 2014
-->