Plasma Proteome Signature of Immune Inhibition is Associated with Cytomegalovirus in People with HIV-1

Abstract

Abstract Background Cytomegalovirus (CMV) is highly prevalent and associated with comorbidities in people with HIV-1 (PWH). CMV contributes to systemic inflammation, but comprehensive analyses of the plasma proteome in PWH with or without CMV are lacking. Methods Plasma proteomes from 59 age- and CD4 count-matched PWH on suppressive antiretroviral therapy (ART) with (CMV+) or without (CMV-) CMV were characterized by inflammation- and cardiometabolic-focused proteomics proximity extension assays. Normalized protein expression values were analyzed using linear mixed effects models, partial least squares-discriminant analysis, and gene set enrichment analysis. T cell phenotypes were assessed by flow cytometry. Results In covariate-unadjusted linear mixed effects models, 118/350 (33.7%) inflammatory and 27/363 (7.4%) cardiometabolic proteins were differentially expressed (FDR-adjusted p<0.05). Proteins most significantly upregulated in CMV+ participants were associated with immune inhibition (e.g., FcRL6, LY9, HLA-DRA), cytotoxic differentiation (e.g., KLRD1, CD70, SLAMF7), and interferon-associated chemotaxis (e.g., CXCL9, CXCL10). Several of the most significantly downregulated proteins in CMV+ PWH were associated with apoptosis (e.g., CASP2, TRIM21, TRAF2). Surface FcRL6 expression was significantly elevated on CD57+CD28- CD8 T cells of CMV+ PWH. Conclusions These data identify a CMV-associated plasma proteomic signature in treated HIV, characterized by immunoinhibitory/cytotoxic programs, supporting targeting CMV to reduce immune dysregulation and related comorbidities in PWH.