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

Abstract

Background. People living with HIV (PLHIV) on antiretroviral therapy (ART) exhibit persistent immune dysregulation and microbial dysbiosis, leading to the development of cardiovascular diseases (CVD). We initially compared plasma proteomic profiles between 205 PLHIV and 120 healthy controls (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.Method. Proximity extension assay technology was utilized to measure 1472 plasma proteins.Markers of systemic inflammation (CRP, D-Dimer, IL6, sCD14, and sCD163) 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 the development of CVD during a 5-year follow-up. Results. PLHIV on ART displayed systemic dysregulation of protein concentrations compared toHCs. Most of the DEPs originated from the intestine and lymphoid tissues, while they enriched in immune-and lipid metabolism-related pathways. Furthermore, we observed that 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 in 5-year follow-up. 4 Conclusions. Our findings suggest a systemic dysregulation of protein concentrations in PLHIV, of which some proteins were associated with CVD development. Most of DEPs originated from the gut and were related to specific gut bacterial species. Trial registration. Cohorts included in this study are part of the Human Functional Genomics Project (HFGP) (www.humanfunctionalgenomics.org). The 2000HIV Human Functional Genomics Partnership Program is registered at ClinicalTrials.gov: (ID: NCT03994835).

The RELT Family of Proteins: An Increasing Awareness of Their Importance for Cancer, the Immune System, and Development

“…RELT was significantly associated with the incidence of myocardial infarction and cardiovascular disease in elderly males from one study [101]. RELT was one of six genes most associated with the development of cardiovascular disease in a 5-year follow-up of persons living with HIV [89]. It is worth noting that modest levels of RELT protein were detected in the kidney [21] and it is therefore possible that RELT influences hypertension, and the risk of myocardial infarction, through its interaction with the OXSR1 [9] and SPAK [27] kinases, as both of these kinases are targets for the treatment of hypertension based on their ability to regulate ion transporters in the kidney [102].…”

“…Proteomic analysis of plasma proteins in an elderly male population indicates that RELT is significantly upregulated in people living with HIV (PLHIV) versus healthy controls when adjusted for age, sex, and smoking status [89]. RELT was upregulated in Langerhans cells and macrophages of PLHIV while immunophenotyping revealed an association of RELT with B cells and neutrophils.…”

Identification of drug candidates targeting monocyte reprogramming in people living with HIV

“…Proteomic profiling of selected markers was performed as described before (53). In brief, venous whole-blood samples were collected in EDTA tubes and centrifuged into plasma, and then stored at -80°C.…”