Mechanisms of Accelerated Liver Fibrosis Progression during HIV Infection

Abstract

With the introduction of antiretroviral therapy (ART), a dramatic reduction in HIV-related morbidity and mortality has been observed. However, it is now becoming increasingly clear that liver-related complications, particularly rapid fibrosis development from ART as well as from the chronic HIV infection itself, are of serious concern to HIV patients. The pathophysiology of liver fibrosis in patients with HIV is a multifactorial process whereby persistent viral replication, and bacterial translocation lead to chronic immune activation and inflammation, which ART is unable to fully suppress, promoting production of fibrinogenic mediators and fibrosis. In addition, mitochondrial toxicity, triggered by both ART and HIV, contributes to intrahepatic damage, which is even more severe in patients co-infected with viral hepatitis. In recent years, new insights into the mechanisms of accelerated fibrosis and liver disease progression in HIV has been obtained, and these are detailed and discussed in this review.

Keywords: Bacterial translocation; HIV; Liver fibrosis; Mitochondrial toxicity.

Fig. 1.. Factors affecting liver fibrosis during human immunodeficiency virus (HIV) infection.

HIV can induce a direct effect on hepatic stellate cells (HSCs), affect T cells and Kupffer cells (KCs), affect hepatocytes through co-receptors, such as CCR5 and CXCR4, and affect mitochondrial DNA. HIV can also increase gut permeability through depletion of intestinal CD4⁺ cells, increasing bacterial translocation. Antiretroviral therapy (ART) can induce insulin resistance and mitochondrial toxicity in the liver. Other factors like hepatitis B (HBV), hepatitis C (HCV) and alcohol consumption can affect hepatocytes’ worsening liver fibrosis.

Fig. 2.. Effects of human immunodeficiency virus (HIV) and antiretroviral therapy (ART) on mitochondrial toxicity.

HIV virus can decrease mitochondrial DNA in CD4⁺ and CD8⁺ T cells. Different ART components can inhibit pol-gamma, acetylate kinase and RNA polymerase related to mitochondria, thereby inhibiting mitochondrial DNA. Decrease in mitochondrial DNA leads to less mitochondria and less beta-oxidation of fatty acids, with an increase in free fatty acids and their deposition in liver parenchyma leading to steatosis. Fat also accumulates in peripheral tissues augmenting insulin resistance (IR), which can also be affected by ART (through inhibition of lipolysis), all of which contributes to steatosis and liver fibrosis.