Hepatic Inflammatory Cytokine mRNA Expression in Hepatitis C Virus-Human Immunodeficiency Virus Co-infection

Summary and Introduction

Although epidemiologic studies have documented that hepatitis C virus (HCV)/human immunodeficiency virus (HIV) co-infected patients have accelerated fibrogenesis, especially those with CD4⁺ cell counts <200 cells/mm³, the pathogenic mechanisms are poorly understood. We investigated whether severe immunodeficiency in co-infection is associated with changes in intrahepatic inflammatory cytokine mRNA levels. We measured interferon (IFN)-γ, tumour necrosis factor-χ, transforming growth factor (TGF)-β₁, interleukin (IL)-4, IL-10, IL-12p35 and IL-12p40 mRNA levels by real-time PCR performed on liver samples from HCV mono-infected (n = 19) and HCV/HIV co-infected (n = 24) patients. Co-infected patients had decreased intrahepatic mRNA levels of IFN-γ (P = 0.09), IL-4 (P = 0.05) and IL-12p35 (P = 0.04) compared with mono-infected patients, while IL-10 was increased (P = 0.07). In co-infected patients, IFN-γ mRNA levels increased linearly with increasing peripheral CD4⁺ cell counts by 1.23 times relative to the calibrator for every 100 CD4⁺ cells/mm³ increase (P = 0.02). No other cytokines were significantly associated with CD4⁺ cell counts. In conclusion, HIV-induced lymphopenia may result in hepatic inflammatory cytokine suppression in HCV/HIV co-infection. Intrahepatic IFN-γ levels are significantly reduced in patients with advanced immunodeficiency. Further studies are needed to assess whether decreased IFN-γ secretion by HCV-specific CD4⁺ cells may account for accelerated fibrogenesis in these patients.

Hepatitis C virus (HCV) infection has been identified as a major cause of morbidity and mortality in human immunodeficiency virus (HIV)-infected patients.^[1,2,3] HCV/HIV co-infected patients demonstrate accelerated fibrogenesis leading to more rapid progression to end-stage liver disease in comparison with HCV mono-infected patients.^[4,5,6] Several epidemiologic studies have reported that patients with CD4⁺ lymphopenia, especially <200 CD4⁺ cells/mm³, have accelerated fibrogenesis^[5,7,8,9] and increased intrahepatic inflammation.^[8] Although inflammation may promote fibrogenesis through cytokine production,^[10,11] few studies have evaluated differences in intrahepatic inflammatory cytokines and cellular inflammation in HCV/HIV co-infected compared with mono-infected patients. While prior studies have observed altered cytokine mRNA levels in co-infected patients,^[12,13,14] data are limited on intrahepatic levels of inflammatory cytokines in immunodeficient co-infected patients.

In a previous study, we used immunohistochemistry to enumerate intrahepatic inflammatory cells in co- and mono-infected patients. We noted decreased numbers of intrahepatic CD4⁺ cells in co-infected compared with mono-infected patients.^[15] In peripheral blood, severe lymphopenia (<300 CD4⁺ cells/mm³) is associated with diminished HCV-specific CD4⁺ cells.^[16] In addition, decreased intrahepatic HCV-specific, CD4⁺ interferon (IFN)-γ secretion has been associated with accelerated fibrogenesis.^[17,18] However, neither the number nor the function of intrahepatic HCV-specific CD4⁺ cells has been assessed in severely immunodeficient co-infected patients. In the present study, we investigated whether severe immune deficiency in co-infection is associated with changes in intrahepatic inflammatory cytokine mRNA levels. We assessed cytokine levels by real-time PCR performed on liver samples from HCV/HIV co-infected and HCV mono-infected patients.

J Viral Hepat. 2008;15(5):331-338. © 2008  Blackwell Publishing