Plasma Proteome Signature of Immune Inhibition Is Associated With Cytomegalovirus in People With HIV-1

Background

Cytomegalovirus (CMV) is highly prevalent and associated with comorbidities in people with HIV-1 (PWH). Cytomegalovirus 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 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 (false discovery rate-adjusted P < .05). Proteins most significantly upregulated in CMV+ participants were associated with immune inhibition (eg, FcRL6, LY9, and HLA-DRA), cytotoxic differentiation (eg, KLRD1, CD70, and SLAMF7), and interferon-associated chemotaxis (eg, CXCL9 and CXCL10). Several of the most significantly downregulated proteins in CMV+ PWH were associated with apoptosis (eg, CASP2, TRIM21, and 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.