Abstract
The pathogenesis of accelerated liver damage in subjects coinfected with hepatitis C virus (HCV) and human immunodeficiency virus type 1 (HIV-1) remains largely unknown. Recent studies suggest that ongoing chronic liver inflammation is responsible for the liver injury in HCV-infected patients. We aimed to determine whether HIV-1 coinfection altered intrahepatic inflammatory profiles in HCV infection, thereby hastening liver damage. We used a real-time RT-PCR-based array to comparatively analyze intrahepatic inflammation gene profiles in liver biopsy specimens from HCV-infected (n = 16), HCV/HIV-1-coinfected (n = 8) and uninfected (n = 8) individuals. We then used human hepatocytes to study the molecular mechanisms underlying alternations of the inflammatory profiles. Compared with uninfected individuals, HCV infection and HCV/HIV-1 coinfection markedly altered expression of 59.5% and 50.0% of 84 inflammation-related genes tested, respectively. Among these genes affected, HCV infection up-regulated the expression of 24 genes and down-regulated the expression of 26 genes, whereas HCV/HIV-1 coinfection up-regulated the expression of 21 genes and down-regulated the expression of 21 genes. Compared with HCV infection, HCV/HIV-1 coinfection did not dramatically affect intrahepatic gene expression profiles of cytokines and their receptors, but profoundly altered expression of several chemokine genes including up-regulation of the CXCR3-associated chemokines. Human hepatocytes produced these chemokines in response to virus-related microbial translocation, viral protein stimulation, and antiviral immune responses.ConclusionsHIV-1 coinfection profoundly alters intrahepatic chemokine but not cytokine profiles in HCV-infected subjects. The altered chemokines may orchestrate the tissue-specific and cell-selective trafficking of immune cells and autoimmunity to accelerate liver disease in HCV/HIV-1 coinfection.
Highlights
human immunodeficiency virus type 1 (HIV-1) and hepatitis C virus (HCV) infections are both major global health problems
Intrahepatic Inflammatory Profiles are Altered in HCV/ HIV-1-Coinfected Individuals Compared to HCV-infected Individuals
The liver biochemistries in HCV infected vs. HCV/HIV1 coinfected subjects were: alkaline phosphatase (ALP) 105650 IU/mL vs. 92630 IU/mL (p = 0.5), alanine aminotransferase (ALT) 88676 IU/mL vs. 55653 IU/mL (p = 0.3), aspartate aminotransferase (AST) 74641 IU/mL vs. 74653 IU/mL (p = 0.9), and total bilirubin 0.960.5 vs. 0.860.5 mg/dL (p = 0.7)
Summary
HIV-1 and HCV infections are both major global health problems. The number of people living with HIV-1 or HCV continues to grow because no vaccine is currently available to protect against either virus. Due to their shared routes of transmission, HIV-1 and HCV coinfection (HCV/HIV-1) is common, affecting approximately 25–33% of HIV-1-infected persons [3]. HIV-1 coinfection accelerates HCV-related liver injury, resulting in faster development of cirrhosis and end-stage liver disease [4]. The accelerated progression of liver disease due to HCV/HIV-1 coinfection has emerged as a leading cause of death in HIV-1-infected persons. The pathogenic mechanisms as to why HCV-associated liver disease is worse in the presence of HIV-1 remain unknown, but could be related to alternations of liver inflammatory profiles, impaired immune responses, and druginduced hepatotoxicity
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