María J. Buzón

Vall d'Hebron Institut de Recerca

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Co-Authors

Meritxell Genescà

Vall d'Hebron Institut de Recerca

Mathias Lichterfeld

Ragon Institute of MGH, MIT and Harvard

Javier Martínez‐Picado

IrsiCaixa

Vicenç Falcó

Vall d'Hebron Institut de Recerca

Judith Grau-Expósito

Universitat Autònoma de Barcelona

Bonaventura Clotet

Universitat Autònoma de Barcelona

Xu G. Yu

Ragon Institute of MGH, MIT and Harvard

Joaquín Burgos

Vall d'Hebron Institut de Recerca

María C. Puertas

Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol

Jordi Navarro

Vall d'Hebron Institut de Recerca

Cooperative Institutions

Universitat Autònoma de Barcelona

177

Vall d'Hebron Institut de Recerca

110

Instituto de Salud Carlos III

Vall d'Hebron Hospital Universitari

Centro de Investigación Biomédica en Red

Hospital Universitari Germans Trias i Pujol

Institut d'Investigació en Ciències de la Salut Germans Trias i Pujol

Ragon Institute of MGH, MIT and Harvard

Universidad Autónoma de Madrid

IrsiCaixa

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NK cell depletion in bispecific antibody therapy is associated with lack of HIV control after ART interruption

Communications Biology (2025)

Nerea Sánchez-Gaona David Perea Adrián Curran Joaquín Burgos Jordi Navarro

HIV infection remains incurable as the virus persists within a latent reservoir of CD4+T cells. Novel approaches to enhance immune responses against HIV are essential for effective control and potential cure of the infection. In this study, we designed a novel tetravalent bispecific antibody (Bi-Ab32/16) to simultaneously target the gp120 viral protein on infected cells, and the CD16a receptor on NK cells. In vitro, Bi-Ab32/16 triggered a potent, specific, and polyfunctional NK-dependent response against HIV-infected cells. Moreover, addition of the Bi-Ab32/16 significantly reduced the latent HIV reservoir after viral reactivation and mediated the clearance of cells harboring intact proviruses in samples from people with HIV (PWH). However, the in vivo preclinical evaluation of Bi-Ab32/16 in humanized mice expressing IL-15 (NSG-Hu-IL-15) revealed a significant decline of NK cells associated with poor virological control after ART interruption. Our study underscores the need to carefully evaluating strategies for sustained NK cell stimulation during ART withdrawal. Bispecific antibody targeting NK cells facilitates clearance of HIV-infected cells in vitro but poses challenges in sustaining NK cell function during ART withdrawal in preclinical models.

Bispecific antibody

10.1038/s42003-025-07651-6

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Evaluation of SARS-CoV-2 Entry, Inflammation and New Therapeutics in Human Lung Tissue Cells

bioRxiv (Cold Spring Harbor Laboratory) (2021)

Judith Grau-Expósito David Perea Marina Suppi Núria Massana Ander Vergara

Abstract The development of physiological models that reproduce SARS-CoV-2 infection in primary human cells will be instrumental to identify host-pathogen interactions and potential therapeutics. Here, using cell suspensions directly from primary human lung tissues (HLT), we have developed a rapid platform for the identification of viral targets and the expression of viral entry factors, as well as for the screening of viral entry inhibitors and anti-inflammatory compounds. The direct use of HLT cells, without long-term cell culture and in vitro differentiation approaches, preserves main immune and structural cell populations, including the most susceptible cell targets for SARS-CoV-2; alveolar type II (AT-II) cells, while maintaining the expression of proteins involved in viral infection, such as ACE2, TMPRSS2, CD147 and AXL. Further, antiviral testing of 39 drug candidates reveals a highly reproducible method, suitable for different SARS-CoV-2 variants, and provides the identification of new compounds missed by conventional systems, such as VeroE6. Using this method, we also show that interferons do not modulate ACE2 expression, and that stimulation of local inflammatory responses can be modulated by different compounds with antiviral activity. Overall, we present a relevant and rapid method for the study of SARS-CoV-2. Graphical Abstract Highlights Ex vivo physiological systems for the study of SARS-CoV-2-host interactions are scarce. Here, we establish a method using primary human lung tissue (HLT) cells for the rapid analysis of cell tropism and identification of therapeutics. HLT cells preserve main cell subpopulations, including alveolar type-2 cells, and expression of SARS-CoV-2 entry factors ACE2, CD147, TMPRSS2 and AXL. HLT cells are readily susceptible to SARS-CoV-2 infection without the need of cell isolation or further cell differentiation. Antiviral testing in HLT cells allows the rapid identification of new drug candidates against SARS-CoV-2 variants, missed by conventional systems. Local inflammation is supported in HLT cells and offers the identification of relevant anti-inflammatory compounds for SARS-CoV-2 infection.

Cell type

Ex vivo

Tissue tropism

Identification

10.1101/2021.04.21.440731

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Citations (2)

Hepatitis C Therapy With Interferon-α and Ribavirin Reduces CD4 T-Cell–Associated HIV-1 DNA in HIV-1/Hepatitis C Virus–Coinfected Patients

The Journal of Infectious Diseases (2013)

Hong Sun María J. Buzón Amy Shaw R. Berg Xu G. Yu

Combined treatment with interferon alpha (IFN-α) and ribavirin (RBV) can effectively cure HCV infection in a significant proportion of patients, but effects of this regimen on cellular reservoirs for human immunodeficiency virus type 1 (HIV-1) are unknown. Here, we show that treatment with IFN-α/RBV led to a moderate but significant and sustained decline of HIV-1 DNA in CD4 T cells from HIV-1/hepatitis C virus–coinfected patients receiving highly active antiretroviral therapy (n = 12). However, in vitro experiments failed to demonstrate an effect of pharmacological doses of IFN-α on HIV-1 reactivation. Together, these data suggest that treatment with IFN-α/RBV can moderately reduce the reservoir of HIV-1–infected CD4 T cells that persists despite suppressive antiretroviral therapy.

Hepatitis C

Regimen

10.1093/infdis/jit628

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Citations (59)

Innate Immune Activity Correlates with CD4 T Cell-Associated HIV-1 DNA Decline during Latency-Reversing Treatment with Panobinostat

Journal of Virology (2015)

Rikke Olesen Selena Viganó Thomas A. Rasmussen Ole S. Søgaard Zhengyu Ouyang

The pharmaceutical reactivation of dormant HIV-1 proviruses by histone deacetylase inhibitors (HDACi) represents a possible strategy to reduce the reservoir of HIV-1-infected cells in individuals treated with suppressive combination antiretroviral therapy (cART). However, the effects of such latency-reversing agents on the viral reservoir size are likely to be influenced by host immune responses. Here, we analyzed the immune factors associated with changes in proviral HIV-1 DNA levels during treatment with the potent HDACi panobinostat in a human clinical trial involving 15 cART-treated HIV-1-infected patients. We observed that the magnitude, breadth, and cytokine secretion profile of HIV-1-specific CD8 T cell responses were unrelated to changes in HIV-1 DNA levels in CD4 T cells during panobinostat treatment. In contrast, the proportions of CD3(-) CD56(+) total NK cells and CD16(+) CD56(dim) NK cells were inversely correlated with HIV-1 DNA levels throughout the study, and changes in HIV-1 DNA levels during panobinostat treatment were negatively associated with the corresponding changes in CD69(+) NK cells. Decreasing levels of HIV-1 DNA during latency-reversing treatment were also related to the proportions of plasmacytoid dendritic cells, to distinct expression patterns of interferon-stimulated genes, and to the expression of the IL28B CC genotype. Together, these data suggest that innate immune activity can critically modulate the effects of latency-reversing agents on the viral reservoir and may represent a target for future immunotherapeutic interventions in HIV-1 eradication studies.Currently available antiretroviral drugs are highly effective in suppressing HIV-1 replication, but the virus persists, despite treatment, in a latent form that does not actively express HIV-1 gene products. One approach to eliminate these cells, colloquially termed the "shock-and-kill" strategy, focuses on the use of latency-reversing agents that induce active viral gene expression in latently infected cells, followed by immune-mediated killing. Panobinostat, a histone deacetylase inhibitor, demonstrated potent activities in reversing HIV-1 latency in a recent pilot clinical trial and reduced HIV-1 DNA levels in a subset of patients. Interestingly, we found that innate immune factors, such as natural killer cells, plasmacytoid dendritic cells, and the expression patterns of interferon-stimulated genes, were most closely linked to a decline in the HIV-1 DNA level during treatment with panobinostat. These data suggest that innate immune activity may play an important role in reducing the residual reservoir of HIV-1-infected cells.

Panobinostat

10.1128/jvi.01484-15

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Citations (83)

Productive HIV-1 infection upregulates CD32 in vitro and in vivo

Journal of Virus Eradication (2017)

C. Serra Peinado Judith Grau-Expósito Vicenç Falcó Meritxell Genescà L.J. Martinez-Picado

10.1016/s2055-6640(20)30541-0

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Effect of the Human Immunodeficiency Virus Type 1 Reverse Transcriptase Polymorphism Leu-214 on Replication Capacity and Drug Susceptibility

Journal of Virology (2009)

María C. Puertas María J. Buzón Anna Artese Stefano Alcaro Luis Menéndez‐Arias

ABSTRACT A negative association between polymorphism Leu-214 and type-1 thymidine analogue mutations (TAM1) and a positive association with a clinically favorable virological response to thymidine analogue-based combination antiretroviral therapy have been described. In this study, the impact of Leu-214 on replication capacity and resistance to zidovudine (ZDV) of viruses containing TAM1 or TAM2 was determined. Leu-214 decreased the growth rate of viruses bearing Tyr-215, as well as their resistance to ZDV. This observation was confirmed by structural and molecular modeling data, suggesting a regulatory role for Leu-214 in the emergence and phenotypic resistance of TAM1.

Thymidine

10.1128/jvi.00487-09

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Citations (13)

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)

Judith Grau-Expósito Carla Serra‐Peinado L. Miguel Jordi Navarro Adrián Curran

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 in situ 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 ex vivo 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 ex vivo 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.IMPORTANCE 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.

10.1128/mbio.00876-17

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Citations (103)

Fracaso de los Agentes Reversores de la Latencia Viral en Reducir los Reservorios del VIH

Scientific Medical Data (2020)

María J. Buzón

10.24175/sbd.2020.000009

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Transcriptional Changes in CD8+ T Cells During Antiretroviral Therapy Intensified With Raltegravir

Carolina Digital Repository (University of North Carolina at Chapel Hill) (2015)

Zhengyu Ouyang María J. Buzón Lu Zheng Hong Sun Xu G. Yu

Raltegravir

10.17615/06xm-gb45

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Intraepithelial CD15 infiltration identifies high-grade anal dysplasia in people with HIV

JCI Insight (2024)

Joaquín Burgos Aleix Benítez-Martínez Cristina Mancebo Núria Massana Antonio Astorga-Gamaza

Men who have sex with men (MSM) with HIV are at high risk for squamous intraepithelial lesion (SIL) and anal cancer. Identifying local immunological mechanisms involved in the development of anal dysplasia could aid treatment and diagnostics. Here we studied 111 anal biopsies obtained from 101 MSM with HIV, who participated in an anal screening program. We first assessed multiple immune subsets by flow cytometry, in addition to histological examination, in a discovery cohort (n = 54). Selected molecules were further evaluated by immunohistochemistry in a validation cohort (n = 47). Pathological samples were characterized by the presence of Resident Memory T cells with low expression of CD103 and by changes in Natural Killer cell subsets, affecting residency and activation. Furthermore, potentially immune suppressive subsets, including CD15+CD16+ mature neutrophils, gradually increased as the anal lesion progressed. Immunohistochemistry confirmed the association between the presence of CD15 in the epithelium and SIL diagnosis, with a sensitivity of 80% and specificity of 71% (AUC 0.762) for the correlation with high-grade SIL. A complex immunological environment with imbalanced proportions of resident effectors and immune suppressive subsets characterizes pathological samples. Neutrophil infiltration, determined by CD15 staining, may represent a valuable pathological marker associated with the grade of dysplasia.

CD15

Squamous intraepithelial lesion

Immunophenotyping

10.1172/jci.insight.175251

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