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

## TL;DR

This study explores how CMV infection affects the immune system in people with HIV, identifying FCRL6 as a potential biomarker for immune activation.

## Contribution

The study identifies FCRL6 as a novel biomarker for immune activation in CMV-seropositive people living with HIV.

## Key findings

- CMV seropositivity increases pro-inflammatory cytokine production in immune cells of PLHIV.
- FCRL6 expression is elevated in CMV-seropositive PLHIV, linked to demethylation and increased gene and protein levels.
- Mendelian randomization confirms a causal relationship between elevated FCRL6 and CMV seropositivity.

## 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.

Cytomegalovirus (CMV) seropositivity exacerbates immune complications in people living with HIV (PLHIV). Here, the authors utilize multi-omics and immune phenotyping data and show that CMV seropositivity induces pro-inflammatory cytokines and further identify FCRL6 as a potential biomarker for immune activation.