Pathogenesis of accelerated fibrosis in HIV/HCV co-infection

Abstract

Human immunodeficiency virus (HIV) infection is a major cause of acceleration of hepatitis C virus-related liver disease, cirrhosis, and death. However, studies of liver disease pathogenesis in HIV/HCV coinfection have thus far been limited. Emerging data support multiple derangements attending HIV coinfection, including increases in profibrogenic cytokine expression and secretion, generation of enhanced oxidative stress, and increases in hepaotcyte apoptosis. These derangements may be further augmented in the presence of increased microbial translocation in the setting of HIV disease. New insight into the mechanisms of HIV/HCV pathogenesis causing accelerated liver fibrosis could lead to new therapeutic strategies designed to retard ths process.

Figure 1.

Proposed pathway of human immunodeficiency virus/hepatitis C virus (HIV/HCV) regulation of hepatic fibrogenesis. HIV and HCV activate reactive oxygen species (ROS) productions in hepatic stellate cells (HSCs) and hepatocytes. ROS stimulates the phosphorylation of p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK). The phosphorylated p38 MAPK, JNK, and p42/44 ERK activate the phosphorylation of NF-κB. The induced NF-κB is then translocated to the nucleus, increasing the expression of profibrogenic genes (eg, transforming growth factor β1[TGF-β1], procollagen α1, and tissue inhibitor of MMPs [TIMP-1]) and inhibiting the production of antifibrogenic genes (eg, MMP-3).