High-throughput proteomic analysis reveals systemic dysregulation in virally suppressed people living with HIV
Nadira Vadaq, Yue Zhang, Wilhelm A.J.W. Vos, Albert L. Groenendijk, Martinus J.T. Blaauw, Louise E. van Eekeren, Maartje Jacobs-Cleophas, Lisa van de Wijer, Jéssica Cristina dos Santos, Muhammad Hussein Gasem, Leo A.B. Joosten, Mihai G. Netea, Quirijn de Mast, Jingyuan Fu, André J.A.M. van der Ven, Vasiliki Matzaraki
Nadira Vadaq, Yue Zhang, Wilhelm A.J.W. Vos, Albert L. Groenendijk, Martinus J.T. Blaauw, Louise E. van Eekeren, Maartje Jacobs-Cleophas, Lisa van de Wijer, Jéssica Cristina dos Santos, Muhammad Hussein Gasem, Leo A.B. Joosten, Mihai G. Netea, Quirijn de Mast, Jingyuan Fu, André J.A.M. van der Ven, Vasiliki Matzaraki
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Clinical Research and Public Health AIDS/HIV

High-throughput proteomic analysis reveals systemic dysregulation in virally suppressed people living with HIV

Abstract

BACKGROUND People living with HIV (PLHIV) receiving antiretroviral therapy (ART) exhibit persistent immune dysregulation and microbial dysbiosis, leading to development of cardiovascular diseases (CVDs). We initially compared plasma proteomic profiles between 205 PLHIV and 120 healthy control participants (HCs) and validated the results in an independent cohort of 639 PLHIV and 99 HCs. Differentially expressed proteins (DEPs) were then associated to microbiome data. Finally, we assessed which proteins were linked with CVD development in PLHIV.METHODS Proximity extension assay technology was used to measure 1,472 plasma proteins. Markers of systemic inflammation (C-reactive protein, D-dimer, IL-6, soluble CD14, and soluble CD163) and microbial translocation (IFABP) were measured by ELISA, and gut bacterial species were identified using shotgun metagenomic sequencing. Baseline CVD data were available for all PLHIV, and 205 PLHIV were recorded for development of CVD during a 5-year follow-up.RESULTS PLHIV receiving ART had systemic dysregulation of protein concentrations, compared with HCs. Most of the DEPs originated from the intestine and lymphoid tissues and were enriched in immune- and lipid metabolism–related pathways. DEPs originating from the intestine were associated with specific gut bacterial species. Finally, we identified upregulated proteins in PLHIV (GDF15, PLAUR, RELT, NEFL, COL6A3, and EDA2R), unlike most markers of systemic inflammation, associated with the presence and risk of developing CVD during 5-year follow-up.CONCLUSION Our findings suggest a systemic dysregulation of protein concentrations in PLHIV; some proteins were associated with CVD development. Most DEPs originated from the gut and were related to specific gut bacterial species.TRIAL REGISTRATION ClinicalTrials.gov NCT03994835.FUNDING AIDS-fonds (P-29001), ViiV healthcare grant (A18-1052), Spinoza Prize (NWO SPI94-212), European Research Council (ERC) Advanced grant (grant 833247), and Indonesia Endowment Fund for Education.

Authors

Nadira Vadaq, Yue Zhang, Wilhelm A.J.W. Vos, Albert L. Groenendijk, Martinus J.T. Blaauw, Louise E. van Eekeren, Maartje Jacobs-Cleophas, Lisa van de Wijer, Jéssica Cristina dos Santos, Muhammad Hussein Gasem, Leo A.B. Joosten, Mihai G. Netea, Quirijn de Mast, Jingyuan Fu, André J.A.M. van der Ven, Vasiliki Matzaraki

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Figure 1

Dysregulation of protein concentrations in PLHIV compared with HCs.

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Dysregulation of protein concentrations in PLHIV compared with HCs. (A) ...
(A) Study overview. (B) PCA of protein levels from the discovery (left: n = 205 PLHIV vs. 120 HCs) and replication cohorts (right: n = 639 PLHIV vs. 99 HCs) using the first 2 principal components. The ellipses were centered on the basis of the median of PC1 and PC2 for each group (PLHIV and HCs) and the median differences between groups were assessed by the Mann-Whitney U test. ***P < 0.0001. (C) Four-quadrant plot of the fold-change of sDEPs (n = 276) in the discovery (x axis; n = 205 PLHIV vs. 102 HCs) and replication cohorts (y axis; n = 639 PLHIV vs. 84 HCs). DE analysis was performed using a linear regression model with age, sex, and smoking status as covariates. Fold-change in the x axis label refers to the difference in the mean of log2 NPX values between PLHIV and HCs. Only proteins with FDR < 0.05 and log2 fold-change ≥ 1.5 are annotated. See also Supplemental Table 4. Var, variation.