*Purpose: Our current understanding of the pathogenesis of BKVN is based primarily on transcriptomics studies. However, proteins are the final effector molecules that mediate tissue injury. Moreover, human tissues show significant spatial, temporal and quantitative differences between mRNA and protein expression. Accordingly, this study seeks to interrogate BKVN tissues using proteomics technology.

*Methods: Tandem mass tag isobaric labeling and label free quantitative profiling were used to interrogate a set of 15 allograft biopsies with equal representation of healthy kidney (HKD), T-cell mediated rejection (TCMR) and BKVN. Data analysis consisted of reporter ion intensity relative quantification, log transformation, quantile normalization, and differential expression (DE) analysis by Limma (p<0.05).

*Results: Using >1.5 fold change and p<0.05 as the defining threshold, 175 proteins upregulated in BKVN compared to HKD included DQB1 MHC class II fragments, protein phosphatase C (PTPRC), histone cluster 1H1 family proteins (HIST1H1D/B), joining chain of multimeric IgA and IgM, protein disulfide isomerase family A member 3, calponin 1 (CNN1), vimentin, hypoxia up-regulated 1, collagen type VI alpha 1 chain, actin related protein 2/3 complex subunit 3 (ARPC3) insulin like growth factor binding protein 7, DnaJ Hsp40, and lysozyme.

The five proteins upregulated in both BKVN and TCMR included ribosomal protein lateral stalk subunit PO (RPLP0), myosin light chain 9 (MYL9), thymosin beta 4 X-linked (TMSP10/TMSB4X), spartin (SPART) and UDP-glucose glycoprotein glucosyltransferase (UGGT1).

Six proteins were downregulated in both HKD and TCMR, namely, SLC2A5 SLC22A8 (solute carrier family), METTL7B (methyltransferase like 7B), APOH (apolipoprotein H), CCDC93 (coiled-coil domain containing 93), and PODXL (podocalyxin like). Notable amongst 11 proteins downregulated only in TCMR were SLC2A5 SLC22A8 (solute carrier family), METTL7B (methyltransferase like 7B APOH (apolipoprotein H), CCDC93 (coiled-coil domain containing 93), and PODXL (podocalyxin like).

*Conclusions: BKV upregulation of MHC class II and immunoglobin related proteins highlights its role in eliciting pathological changes mimicking acute rejection. Alterations in proteins of the histone (H1ST1HID/B) and post-translational protein modification pathways (PTPRC, METTL7B, UGGT1) stresses the importance of epigenetics mechanisms in the viral life cycle. Proteins relevant to fibrogenesis (COL6A3, CNN1, VIM), inflammatory influx (lysozyme), viral replication (DnaJ Hsp40) and intracellular transport (ARPC3) were also affected. No DE proteins could distinguish TCMR from BKVN.

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