Effect of cytomegalovirus and Epstein-Barr virus replication on intestinal mucosal gene expression and microbiome composition of HIV-infected and uninfected individuals

Background: HIV-infection is associated with dramatic changes in the intestinal mucosa. The impact of other viral pathogens is unclear. Methods: One hundred and eight (108) biopsies from left and right colon (n=79) and terminal ileum (n=29) were collected from 19 HIV-infected and 22 HIV-uninfected participants. Levels of cytomegalovirus (CMV) and Epstein-Barr virus (EBV) DNA were measured by droplet digital PCR. Mucosal gene expression was measured via multiplex-assay. Microbiome analysis was performed using bacterial 16S-rDNA-pyrosequencing. The effect of CMV and EBV replication on the microbiome composition and mRNA-expression of selected cytokines (IL-6, IFN-γ, IL-1β, CCL2, IL-8, and IFN-β1) was evaluated. Results: Overall, CMV and EBV were detected in at least one intestinal site in 60.5 and 78.9% of participants, respectively. HIV-infected individuals demonstrated less detectable CMV (P=0.04); CMV was more frequently detected in terminal ileum than colon (P=0.04). Detectable EBV was more frequent among HIV-infected (P=0.05) without differences by intestinal site. The number of operational taxonomic units did not differ by CMV or EBV detection status. Among HIV-infected participants, higher CMV was only associated with lower relative abundance of Actinobacteria in the ileum (P=0.03). Presence of CMV was associated with upregulated expression of all selected cytokines in the ileum (all P=0.02) and higher expression of IL-8 and IFN-β1 in the colon (all P<0.05) of HIV-uninfected participants, but not among HIV-infected. EBV had no effect on cytokine expression or microbiome composition whatsoever. Conclusion: These results illustrate a complex interplay among HIV-infection, intestinal CMV replication, and mucosal gut environment, and highlight a possible modulatory effect of CMV on the microbial and immune homeostasis.