Chronic immune activation is a distinguishing feature of liver and PBMC gene signatures from HCV/HIV coinfected patients and may contribute to hepatic fibrogenesis

Abstract

Hepatitis C virus/human immunodeficiency virus (HCV/HIV) coinfected patients demonstrate accelerated progression to severe liver injury in comparison to HCV monoinfected patients, although the underlying mechanisms are unclear owing to infection of separate tissue compartments with two distinct viral pathogens. Microarray analysis of paired liver biopsy and peripheral blood mononuclear cell (PBMC) specimens from HCV/HIV coinfected and HCV monoinfected patients identified a gene expression signature associated with increased inflammation and immune activation that was present only in liver and PBMC samples from coinfected patients. We also identified in these samples liver- and PBMC-specific signatures enriched with fibrogenic/hepatic stellate activation and proinflammatory genes, respectively. Finally, Bayesian networks were constructed by assimilating these data with existing data from liver and PBMC samples from other cohorts, augmenting enrichment of biologically important pathways and further indicating that chronic immune activation in HCV/HIV coinfection may exacerbate liver disease progression in coinfected patients.

Differential regulation of cytotoxicity pathway discriminating between HIV, HCV mono and co-infection identified by transcriptome profiling of PBMCs

“…Under the category of immune system, the most unique finding in our study is the significant up-regulation of cytotoxicity pathway in the former versus the latter group across the 3 pairwise comparisons (HH versus HIV, HH versus HCV, HIV versus HCV; FDR from <0.001 to 0.019; Figure 3; Table 2). Our study is the first to report the significant alterations of this pathway differentiating between HIV, HCV mono-and co-infection, which is also supported by previous findings in HIV/HCV co-infection [30,31,33,34]. Recently, two PBMC studies have implicated this pathway.…”

“…Recently, two PBMC studies have implicated this pathway. One of them reported its enrichment in the significantly up-regulated genes in co-infected patients versus controls [34], and the other showed NK cell signaling in the expanded network constructed from the gene signature in HH versus HCV group [30]. In addition, the up-regulation of cytotoxicity pathway in HH versus HIV as well as in HIV versus HCV has been found in CD4+ T cells [31], and high percentages of cytotoxic CD8+ T cells associated with liver fibrosis in co-infected patients have been detected by the flow cytometry study [33].…”

“…Research by PCR and multiplex assays has revealed that in co-infected versus mono-infected individuals, the former had decreased levels of inflammatory cytokines (IL4, IL8, IL10, IL12, TNF-α, and IFN-γ), increased levels of TGF-β [25,26], impaired response to IFN-α [27], and the association of IFN-γ production with CD4+ T cell counts [25,28]. While PCR studies mainly focused on cytokines, microarray analyses enabled a genome-wide view of transcriptome dysregulations by showing a range of important biological themes associated with the co-infection, including aberrant immune activation, regulation, and differentiation, impaired innate immunity, and dysfunctions of NK and dendritic cells in liver biopsies and PBMCs from co-infected patients [29,30]. Recently, two studies have also demonstrated the dysregulation of cell cycle and metabolism in T cell subsets from co-infected individuals [31,32].…”

“…To date, only two studies have focused on transcriptomes of PBMCs from HIV, HCV mono-and co-infected individuals [29,30]. While the study by Rasmussen et al has compared the transcriptomes of PBMCs only between HCV infected versus HCV and HIV co-infected individuals, the analysis by Kottilil et al has centered on gene clusters based on differentially expressed genes (DEGs).…”

MicroRNAs, Hepatitis C Virus, and HCV/HIV-1 Co-Infection: New Insights in Pathogenesis and Therapy

“…On the other hand, HIV-1 infection of CD4+ T cells has a profound effect in impairing adaptive immune responses towards HCV infected cells contributing to poor natural clearance of the virus [123]. A recent study has suggested that the chronic immune activation characteristic of HIV-1 infection and progression to AIDS [124,125] is a distinguishing feature of the host response to HCV/HIV-1 co-infection [126]. …”