Effect of CMV and EBV 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: Eighty biopsies from left and right colon (n=63) and terminal ileum (n = 17) were collected from 19 HIV-infected and 22 HIV-uninfected subjects. Levels of cytomegalovirus (CMV) and Epstein Barr Virus (EBV) DNA were measured by droplet-digital (dd)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 IFN-β1) was evaluated.

RESULTS: Overall, CMV and EBV were detected in at least one intestinal site in 60.5% and 78.9% of subjects, 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 subjects, higher CMV was only associated with lower relative abundance of Actinobacteria in the ileum (p = 0.03). Presence of CMV was associated with up-regulated expression of all selected cytokines in the ileum (p < 0.02) and higher expression of IL-8 and IFN-β1 in the colon (P < 0.05) of HIV-uninfected subjects, but not among HIV-infected. EBV had no effect on cytokine expression or microbiome composition whatsoever.

CONCLUSIONS: These results illustrate a complex interplay between HIV-infection, intestinal CMV replication and mucosal gut environment, and highlight a possible modulatory effect of CMV on the microbial and immune homeostasis.