Article ; Online: Plasma proteomic profiling identifies CD33 as a marker of HIV control in natural infection and after therapeutic vaccination.
2023 Volume 95, Page(s) 104732
Abstract: 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 ... ...
| Abstract | 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. |
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| MeSH term(s) | Humans ; CD4-Positive T-Lymphocytes ; HIV Infections/blood ; HIV Infections/drug therapy ; HIV Infections/genetics ; HIV Infections/immunology ; HIV Seropositivity ; HIV-1/genetics ; HIV-1/physiology ; Leukocytes, Mononuclear ; Proteome ; Proteomics ; Sialic Acid Binding Ig-like Lectin 3/blood ; Sialic Acid Binding Ig-like Lectin 3/genetics ; Sialic Acid Binding Ig-like Lectin 3/immunology ; Vaccination ; Viral Load/drug effects ; Viral Load/genetics ; Viral Load/immunology ; Anti-HIV Agents ; Biomarkers/blood ; Biomarkers/metabolism |
| Chemical Substances | Proteome ; Sialic Acid Binding Ig-like Lectin 3 ; romidepsin (CX3T89XQBK) ; Anti-HIV Agents ; CD33 protein, human ; Biomarkers |
| Language | English |
| Publishing date | 2023-07-26 |
| Publishing country | Netherlands |
| Document type | Clinical Trial, Phase I ; Journal Article |
| ZDB-ID | 2851331-9 |
| ISSN | 2352-3964 |
| ISSN (online) | 2352-3964 |
| DOI | 10.1016/j.ebiom.2023.104732 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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