Abstract
Liver fibrosis is accelerated in patients coinfected with hepatitis C virus and human immunodeficiency virus (HIV), compared with HCV monoinfected patients, although the underlying mechanisms are unknown. We hypothesize that T cells expressing the HIV co-receptor, chemokine receptor 5 (CCR5), preferentially migrate to the inflamed liver and contribute to enhanced fibrogenesis. We compared the peripheral and intrahepatic CCR5 expression on CD4+ and CD8+ T cells in 21 HIV/HCV-coinfected patients with 14 chronic HCV monoinfected patients. Using 12-color flow cytometry, phenotypic and functional characterization of CCR5+ and negative cells pre- and post-stimulation with HCV genotype specific overlapping pooled peptides was conducted. Patients with HIV/HCV coinfection had significantly more CD4+CCR5+ and CD8+CCR5+ T cells in the liver as compared with peripheral blood (p = 0.0001 for both). Compared with patients with HCV monoinfection, patients with HIV/HCV coinfection also had fewer peripheral CD4+CCR5+ and CD8+CCR5+ T cells (p = 0.02, p = 0.001 respectively), but more intrahepatic CD4+CCR5+ and CD8+CCR5+ cells (p = 0.0001 for both). Phenotypic analysis of CCR5+ sorted cells demonstrated an increased expression of markers of exhaustion, senescence, immune activation and liver homing (PD1, CD57, CD38, HLADR, and CXCR3). Post-stimulation with HCV peptides, CCR5+ T cells secreted more proinflammatory and profibrogenic cytokines and chemokines rather than antiviral cytokines. Phenotypic and functional analyses of CCR5+ T cells in HIV/HCV-coinfected patients revealed a pathogenic role for CCR5+ T cells in hepatic fibrogenesis. These cells are functionally proinflammatory, pro-fibrogenic and preferentially accumulate in liver, accelerating fibrosis. These findings suggest that targeting CCR5 may be a therapeutic strategy for be ameliorating liver fibrosis.
Highlights
We found that chemokine receptor 5 (CCR5) expressing CD4+ and CD8+ T cells from coinfected patients had a higher percentage of CXCR3 expression than CCR5 negative cells (CD4: p = 0.002; CD8: p = 0.01; Figure 2B)
Our study presents a possible CCR5-based mechanism for the enhanced hepatic fibrogenesis observed in human immunodeficiency virus (HIV)/hepatitis C virus (HCV)-coinfected patients
Our findings suggest greater fibrogenesis observed in HIV/HCV-coinfected patients
Summary
HIV/HCV coinfection increases the risk of developing end-stage liver disease or cirrhosis by 2.9 times and accelerates the development of liver fibrosis as compared with HCV monoinfection [3]. (CCR5) belongs to a large family of chemokine receptors that orchestrate the recruitment, migration and activation of mononuclear cells in liver inflammation. The intrahepatic enrichment of CCR5+ lymphocytes in HCV infection has been reported, suggesting a role for inflammatory cell migration to the liver mediated by CC chemokines [18]. We hypothesized that HIV/HCV coinfection augments the preferential migration of CCR5+ T cells to the inflamed liver, enhancing fibrogenesis. We compared the differences in phenotypic, homing, functional and secretory characteristics associated with CCR5 positivity in patients with HIV/HCV coinfection and compared these with HCV and HIV monoinfection
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