Plasma proteomic profiling identifies CD33 as a marker of HIV control in natural infection and after therapeutic vaccinationResearch in context
Clara Duran-Castells,
Anna Prats,
Bruna Oriol-Tordera,
Anuska Llano,
Cristina Galvez,
Javier Martinez-Picado,
Ester Ballana,
Edurne Garcia-Vidal,
Bonaventura Clotet,
Jose A. Muñoz-Moreno,
Thomas Hanke,
José Moltó,
Beatriz Mothe,
Christian Brander,
Marta Ruiz-Riol
Affiliations
Clara Duran-Castells
IrsiCaixa AIDS Research Institute Badalona, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Universitat Autònoma de Barcelona, Spain
Anna Prats
Fight Infections Foundation and Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
Bruna Oriol-Tordera
IrsiCaixa AIDS Research Institute Badalona, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Universitat Autònoma de Barcelona, Spain
Anuska Llano
IrsiCaixa AIDS Research Institute Badalona, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
Cristina Galvez
IrsiCaixa AIDS Research Institute Badalona, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
Javier Martinez-Picado
IrsiCaixa AIDS Research Institute Badalona, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain; Catalan Institution for Research Advanced Studies (ICREA), Barcelona, Spain; CIBER de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain
Ester Ballana
IrsiCaixa AIDS Research Institute Badalona, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
Edurne Garcia-Vidal
IrsiCaixa AIDS Research Institute Badalona, Hospital Universitari Germans Trias i Pujol, Badalona, Spain
Bonaventura Clotet
IrsiCaixa AIDS Research Institute Badalona, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Fight Infections Foundation and Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain
Jose A. Muñoz-Moreno
Fight Infections Foundation and Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Faculty of Psychology and Education Sciences, Universitat Oberta de Catalunya (UOC), Barcelona, Spain
Thomas Hanke
The Jenner Institute, University of Oxford, Oxford OX3 7DQ, UK; Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto, Japan
José Moltó
Fight Infections Foundation and Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; CIBER de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain
Beatriz Mothe
IrsiCaixa AIDS Research Institute Badalona, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Fight Infections Foundation and Infectious Diseases Department, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain; CIBER de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain
Christian Brander
IrsiCaixa AIDS Research Institute Badalona, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; Universitat Autònoma de Barcelona, Spain; University of Vic-Central University of Catalonia (UVic-UCC), Vic, Spain; Catalan Institution for Research Advanced Studies (ICREA), Barcelona, Spain; CIBER de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain
Marta Ruiz-Riol
IrsiCaixa AIDS Research Institute Badalona, Hospital Universitari Germans Trias i Pujol, Badalona, Spain; CIBER de Enfermedades Infecciosas (CIBERINFEC), Madrid, Spain; Corresponding author. IrsiCaixa AIDS Research Institute Badalona, Hospital Universitari Germans Trias i Pujol, Badalona, Spain.
Summary: Background: Biomarkers predicting the outcome of HIV-1 virus control in natural infection and after therapeutic interventions in HIV-1 cure trials remain poorly defined. The BCN02 trial (NCT02616874), combined a T-cell vaccine with romidepsin (RMD), a cancer-drug that was used to promote HIV-1 latency reversal and which has also been shown to have beneficial effects on neurofunction. We conducted longitudinal plasma proteomics analyses in trial participants to define biomarkers associated with virus control during monitored antiretroviral pause (MAP) and to identify novel therapeutic targets that can improve future cure strategies. Methods: BCN02 was a phase I, open-label, single-arm clinical trial in early-treated, HIV infected individuals. Longitudinal plasma proteomes were analyzed in 11 BCN02 participants, including 8 participants that showed a rapid HIV-1 plasma rebound during a monitored antiretroviral pause (MAP-NC, ‘non-controllers’) and 3 that remained off ART with sustained plasma viremia <2000 copies/ml (MAP-C, ‘controllers’). Inflammatory and neurological proteomes in plasma were evaluated and integration data analysis (viral and neurocognitive parameters) was performed. Validation studies were conducted in a cohort of untreated HIV-1+ individuals (n = 96) and in vitro viral replication assays using an anti-CD33 antibody were used for functional validation. Findings: Inflammatory plasma proteomes in BCN02 participants showed marked longitudinal alterations. Strong proteome differences were also observed between MAP-C and MAP-NC, including in baseline timepoints. CD33/Siglec-3 was the unique plasma marker with the ability to discriminate between MAPC-C and MAP-NC at all study timepoints and showed positive correlations with viral parameters. Analyses in an untreated cohort of PLWH confirmed the positive correlation between viral parameters and CD33 plasma levels, as well as PBMC gene expression. Finally, adding an anti-CD33 antibody to in vitro virus cultures significantly reduced HIV-1 replication and proviral levels in T cells and macrophages. Interpretation: This study indicates that CD33/Siglec-3 may serve as a predictor of HIV-1 control and as potential therapeutic tool to improve future cure strategies. Funding: Spanish Science and Innovation Ministry (SAF2017-89726-R and PID2020-119710RB-I00), NIH (P01-AI131568), European Commission (GA101057548) and a Grifols research agreement.