Human immunodeficiency virus and hepatotropic viruses comorbidities as the inducers of liver injury progression

Hepatotropic viruses induced hepatitis progresses much faster and causes more liver-related health problems in people co-infected with human immunodeficiency virus(HIV). Although treatment with antiretroviral therapy has extended the life expectancy of people with HIV, liver disease induced by hepatitis B virus(HBV) and hepatitis C virus(HCV) causes significant numbers of non-acquired immune deficiency syndrome(AIDS)-related deaths in coinfected patients. In recent years, new insights into the mechanisms of accelerated fibrosis and liver disease progression in HIV/HCV and HIV/HBV co-infections have been reported. In this paper, we review recent studies examining the natural history and pathogenesis of liver disease in HIV-HCV/HBV co-infection in the era of direct acting antivirals(DAA) and antiretroviral therapy(ART). We also review the novel therapeutics for management of HIV/HCV and HIV/HBV coinfected individuals.

Liver as a target of human immunodeficiency virus infection

Liver injury is a characteristic feature of human immunodeficiency virus(HIV) infection, which is the second most common cause of mortality in HIV-infected patients. Now it is recognized that liver plays a key role in HIV infection pathogenesis. Antiretroviral therapy(ART), which suppresses HIV infection in permissive immune cells, is less effective in hepatocytes, thereby making these cells a silent reservoir of HIV infection. In addition to direct hepatotoxic effects of HIV, certain ART treatment modalities provide hepatotoxic effects. The exact mechanisms of HIV-triggered chronic hepatitis progression are not elucidated, but the liver is adversely affected by HIV-infection and liver cells are prominently involved in HIV-elicited injury. These effects are potentiated by second hits like alcohol. Here, we will focus on the incidence of HIV, clinical evidence of HIVrelated liver damage, interactions between HIV and liver cells and the role of alcohol and co-infection with hepatotropic viruses in liver inflammation and fibrosis progression.

Role of alcohol in pathogenesis of hepatitis B virus infection

Hepatitis B virus(HBV)and alcohol abuse often contribute to the development of end-stage liver disease.Alcohol abuse not only causes rapid progression of liver disease in HBV infected patients but also allows HBV to persist chronically.Importantly,the mechanism by which alcohol promotes the progression of HBVassociated liver disease are not completely understood.Potential mechanisms include a suppressed immune response,oxidative stress,endoplasmic reticulum and Golgi apparatus stresses,and increased HBV replication.Certainly,more research is necessary to gain a better understanding of these mechanisms such that treatment(s)to prevent rapid liver disease progression in alcohol-abusing HBV patients could be developed.In this review,we discuss the aforementioned factors for the higher risk of liver diseases in alcohol-induced HBV pathogenies and suggest the areas for future studies in this field.

Aberrant post-translational protein modifications in the pathogenesis of alcohol-induced liver injury

It is likely that the majority of proteins will undergo post-translational modification, be it enzymatic or non-enzymatic. These modified protein(s) regulate activity, localization and interaction with other cellular molecules thereby maintaining cellular hemostasis. Alcohol exposure significantly alters several of these post-translational modifications leading to impairments of many essential physiological processes. Here, we present new insights into novel modifications following ethanol exposure and their role in the initiation and progression of liver injury. This critical review condenses the proceedings of a symposium at the European Society for the Biomedical Research on Alcoholism Meeting held September 12-15, 2015, in Valencia, Spain.

Prolonged feeding with guanidinoacetate, a methyl group consumer, exacerbates ethanol-induced liver injury

AIM To investigate the hypothesis that exposure to guanidinoacetate(GAA, a potent methyl-group consumer) either alone or combined with ethanol intake for a prolonged period of time would cause more advanced liver pathology thus identifying methylation defects as the initiator and stimulator for progressive liver damage.METHODS Adult male Wistar rats were fed the control or ethanolLieber De Carli diet in the absence or presence of GAA supplementation. At the end of 6 wk of the feeding regimen, various biochemical and histological analyses were conducted. RESULTS Contrary to our expectations, we observed that GAA treatment alone resulted in a histologically normal liver without evidence of hepatosteatosis despite persistence of some abnormal biochemical parameters. This protection could result from the generation of creatine from the ingested GAA. Ethanol treatment for 6 wk exhibited changes in liver methionine metabolism and persistence of histological and biochemical defects as reported before. Further, when the rats were fed the GAA-supplemented ethanol diet, similar histological and biochemical changes as observed after 2 wk of combined treatment, including inflammation, macroand micro-vesicular steatosis and a marked decrease in the methylation index were noted. In addition, rats on the combined treatment exhibited increased liver toxicity and even early fibrotic changes in a subset of animals in this group. The worsening liver pathology could be related to the profound reduction in the hepatic methylation index, an increased accumulation of GAA and the inability of creatine generated to exert its hepato-protective effects in the setting of ethanol.CONCLUSION To conclude, prolonged exposure to a methyl consumer superimposed on chronic ethanol consumption causes persistent and pronounced liver damage.

Obeticholic acid attenuates human immunodeficiency virus/alcohol metabolism-induced pro-fibrotic activation in liver cells

BACKGROUND The morbidity and mortality of human immunodeficiency virus(HIV)-infection is often associated with liver disease,which progresses slowly into severe liver dysfunction.There are multiple insults which exacerbate HIV-related liver injury,including HIV-associated dysregulation of lipid metabolism and fat turnover,coinfections with hepatotropic viruses and alcohol abuse.As we reported before,exposure of hepatocytes to HIV and alcohol metabolites causes high oxidative stress,impairs proteasomal and lysosomal functions leading to accumulation of HIV in these cells,which end-ups with apoptotic cell death and finally promotes development of liver fibrosis.AIM To study whether obeticholic acid(OCA)prevents HIV/ethanol metabolisminduced hepatotoxicity and subsequent activation of hepatic stellate cells(HSC)by HIV+apoptotic hepatocyte engulfment.METHODS Huh7.5-CYP(RLW)cells were exposed to HIV and acetaldehyde-generating system(AGS)in the presence or absence of OCA.In the cells,we measured the expression of HIV-related markers:HIVgagRNA-by real-time polymerase chain reaction(PCR),p24-by western blot,HIV DNA-by semi-nested PCR,integrated HIV DNA-by ddPCR.Lysosomal and proteasomal activities were measured using fluorometrically-labeled substrates.For hepatocyte apoptosis,cleaved caspase 3 and cleaved PARP were visualized by western blot and cytokeratin 18-by M30 ELISA-in supernatants.Apoptotic bodies were generated from untreated and HIV-treated RLW cells exposed to UV light.Pro-fibrotic activation of HSC was characterized by Col1A1 and transforming growth factor-βmRNAs,while inflammasome activation-by NLRP3,caspase 1,interleukin(IL)-6,IL-1βmRNA levels.RESULTS In RLW cells,OCA treatment attenuated HIV-AGS-induced accumulation of HIVgagRNA,HIV DNA and p24.OCA suppressed reactive oxygen species production and restored chymotrypsin-like proteasome activity as well as cathepsin B lysosome activity.OCA also decreased HIV-AGS-triggered apoptosis in RLW cells.Exposure of HIV-containing apoptotic hepatocytes to HSC prevented activation of inflammasome and induced pro-fibrotic activation in these cells.CONCLUSION We conclude that by suppressing oxidative stress and restoring proteasomal and lysosomal functions impaired by HIV and ethanol metabolism,OCA decreases accumulation of HIV in hepatocytes,leading to down-regulation of apoptosis in these cells.In addition,OCA reverses pro-fibrotic and inflammasome-related activation of HSC triggered by engulfment of HIV-containing apoptotic hepatocytes,potentially contributing to suppression of liver fibrosis development.