Unravelling molecular signatures and causal factors underlying latent Cytomegalovirus infection among people living with HIV

CMV seropositivity does not lead to severe pathology in healthy individuals, but it 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 1887 PLHIV, by utilizing multi-omics and deep immune phenotyping datasets. We observed prominent CMV-induced signatures at the DNA methylome and transcriptome levels that were related to immune functions in PLHIV. High FCRL6 expression is a promising biomarker for immune activation in latent CMV infection, underlied by the demethylation of FCRL6 and up-regulation of gene expression and plasma protein concentrations in CMV-seropositive PLHIV. Furthermore, the host genetics-driven elevation in both gene and protein expression of FCRL6 was associated with latent CMV infection. We also identified a significant CMV-susceptibility locus associated with cytokine production capacity and protein abundance.