Proteomic Analysis of Hepatic Fibrosis in HIV-Associated NAFLD Demonstrates Upregulation of Immune Response and Tissue Repair Pathways.

BACKGROUND
HIV-associated NAFLD is characterized by a high prevalence of hepatic fibrosis as a strong clinical predictor of all-cause and liver-specific mortality.


METHODS
We leveraged data from a recent clinical trial to define the circulating proteomic signature of hepatic fibrosis in HIV-associated NAFLD. 183 plasma proteins within two high-multiplex panels were quantified at baseline and 12-months using proximity extension assays (Olink Cardiovascular III, Immuno-Oncology).


RESULTS
Twenty proteins were upregulated at baseline among participants with fibrosis stages 2-3 versus 0-1 (P ≤ 0.01, FDR ≤ 0.10). Proteins most differentially expressed included MMP-2 (P = 0.0004), IGFBP-7 (P = 0.001), and COL1A1 (P = 0.001). Proteins were enriched within pathways such as response to tumor necrosis factor (FDR = 1.03e-16), aminopeptidase activity (FDR = 1.20e-5), and positive regulation of apoptotic process (FDR = 8.17e-6). Key proteins also were found to directly relate to visceral adiposity and glucose intolerance, and to inversely correlate with CD4+ T-cell count. Within the placebo-treated arm, 11 proteins differentially increased among individuals with hepatic fibrosis progression over 12-months (P < 0.05).


CONCLUSIONS
Among individuals with HIV-associated NAFLD, hepatic fibrosis was associated with a distinct proteomic signature involving upregulation of tissue repair and immune response pathways. These findings enhance our understanding of potential mechanisms and biomarkers of hepatic fibrosis in HIV.