What question did this study set out to answer?

The central goal is to evaluate how CMV seropositivity influences immune system dynamics in individuals living with HIV.

March 27, 2026Open Access

Molecular signatures and causal factors underlying latent cytomegalovirus infection among people living with HIV (PLHIV)

Key Points

The central goal is to evaluate how CMV seropositivity influences immune system dynamics in individuals living with HIV.
Utilized multi-omics and deep immune phenotyping datasets from 1,887 PLHIV.
Measured immune cell profiles from whole blood and cytokine production from PBMCs.
Analyzed 5 layers of omics data, including genomics and transcriptomics.
Conducted Mendelian randomization analyses to assess causal relationships.
Increased pro-inflammatory cytokine production was observed in CMV-seropositive PLHIV.
High FCRL6 expression emerged as a promising biomarker for immune activation.
Significant associations were found linking FCRL6 expression and latent CMV infection.
A CMV-seroprevalence locus correlated with cytokine production capacity.

Abstract

Abstract CMV seropositivity contributes to medical complications in people living with HIV (PLHIV). This study provides a comprehensive evaluation of how CMV seropositivity shapes the immune system of 1,887 PLHIV, by utilizing multi-omics and deep immune phenotyping datasets. The study measured the immune cell profiles from whole blood, and the cytokine production of PBMCs exposed to various ex-vivo stimuli. We observed an increase in pro-inflammatory cytokine production of circulating immune cells and differences in phenotype of innate-like lymphocyte populations associated with CMV seropositivity. This study also measured 5-omics layers, including genomics, DNA methylation, transcriptomics, and plasma protein and metabolites. The DNA methylome and transcriptome demonstrated prominent CMV-induced signatures related to immune functions in PLHIV. Particularly, high FCRL6 expression is a promising biomarker for immune activation, underlined by the demethylation of FCRL6 and up-regulation of gene expression and plasma protein concentrations in CMV-seropositive PLHIV. Host genetics-driven elevation in both gene and protein expression of FCRL6 was also associated with latent CMV infection. A significant CMV-seroprevalence locus was associated with cytokine production capacity and protein abundance. Mendelian randomization analyses demonstrated a causal relationship between elevated FCRL6 expression and CMV seropositivity.

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