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 4

Plasma proteomic signatures of CVD in PLHIV.

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Plasma proteomic signatures of CVD in PLHIV. (A) Circular heatmap of ass...
(A) Circular heatmap of associations of plasma proteins and CVD in PLHIV from the discovery (n = 205) and replication (n = 639) cohorts. sDEPs are highlighted in red. The associations were explored using linear regression corrected for age, sex, BMI, and smoking status. Only significant associations in the discovery (P < 0.05) and/or replication cohort (FDR < 0.05) are shown. (B) Forest plot showing positive associations between proteins and CVD events in PLHIV in the discovery cohort (P < 0.05; n = 205). P values were calculated using a binomial logistic regression model adjusted for age, sex, BMI, smoking status, and the presence of dyslipidemia, hypertension, and type 2 diabetes at baseline. The relative effects of protein concentration are presented as ORs with 95% CIs. See also Supplemental Table 10. (C) Venn diagram showing the number of shared proteins identified in 3 groups: (i) sDEPs, (ii) proteins associated with the presence of CVD at baseline, and (iii) risk of developing CVD events during 5-year follow-up.