In this process, Kupffer cells are induced to produce cytokines, such as tumor necrosis factor (TNF), interleukin (IL)-1 and IL-6, which are pro-inflammatory mediators that promote liver fibrosis by directly activating HSCs or by priming and recruiting other leukocyte populations.46,47 Similar to infection of CD4+ T cells, HIV can also directly infect Kupffer cells and promote release of pro-fibrotic mediators.48 However, one study reported that HIV reduces the number of Kupffer cells in the liver via unknown mechanisms.49 This HIV-induced loss Rabbit polyclonal to ZNF33A of Kupffer cells could limit the ability of these cells to directly activate HSCs, but likely leads to higher levels of circulating microbial products, which in turn can affect immune responses, promoting inflammation. One of the most well-known pro-fibrogenic mediators is TGF-, which is produced by Kupffer cells in response to TLR ligation upon exposure to microbial compounds.50 Indeed, many studies have reported a positive correlation between liver fibrosis and serum TGF- concentrations, intrahepatic TGF- mRNA levels as well as strong immunohistochemical staining for TGF- in liver tissue.51,52 TGF- directly activates HSC to promote fibrosis, but also plays a homeostatic role to prevent excessive damage by potently suppressing the function of natural killer (NK) cells and T cells, leading to decreased hepatocyte apoptosis and release of HSC-activating mediators.53 Studies showing a clear impact of bacterial translocation on liver fibrosis have been performed in HIV/HCV co-infected patients.54 A recent study in HIV mono-infected individuals showed increased levels of soluble CD14 correlating with fibrosis, suggesting activation of monocytes in response to translocation; however, more studies are necessary to further clarify this concept.5 Mitochondrial dysfunction and toxicity HIV itself can induce mitochondrial toxicity. mechanisms of accelerated fibrosis and liver disease progression in HIV has been obtained, and these are detailed and discussed in this review. strong class=”kwd-title” Keywords: HIV, Liver fibrosis, Mitochondrial toxicity, Bacterial translocation Introduction Liver disease is a major cause of morbidity and the main cause of mortality, independent of acquired immunodeficiency syndrome (AIDS), in persons infected with the human immunodeficiency virus (HIV), with liver fibrosis being a highly significant contributor.1 Although HIV co-infection with hepatitis B virus (HBV) or hepatitis C virus (HCV) is frequent, there is mounting evidence of an increased risk in liver-related morbidity and mortality in the absence EPZ020411 hydrochloride of viral hepatitis.2,3 Cross-sectional studies using liver stiffness measurement (LSM) by transient elastography have shown a significant degree of fibrosis among HIV patients, from 17% in one study to a staggering 41% in a recent study that used lower cutoff values of LSM, although both studies involved patients without viral hepatitis.4,5 Moreover, liver fibrosis progression is accelerated during HIV and HCV co-infection. An analysis using paired liver biopsies showed progression of at least one fibrosis stage (METAVIR) in 34% of HIV/HCV co-infected individuals over a 2.5-year period.6 Hepatic fibrosis is a dynamic process initiated by liver injury that results in increased deposition of extracellular matrix proteins in the space of Disse, the area in between the hepatocytes and the liver sinusoids, which is mainly inhabited by hepatic stellate cells (HSCs).7,8 Accumulation of extracellular matrix proteins and their decreased removal by matrix metalloproteinases results in a progressive replacement of the liver parenchyma by scar tissue, leading to liver fibrosis and its complications.9 Activation of HSCs is a key event in the process leading to excessive deposition of extracellular matrix proteins and the subsequent fibrosis. This activation of HSCs is triggered by numerous events, such as the release of cellular components by injured hepatocytes, lipid accumulation, the secretion of reactive oxygen species (ROS) produced by macrophages, and exposure to cytokines produced by intrahepatic macrophages, lymphocytes and endothelial cells.10 In this review, we summarize and comment on the different potential mechanisms and multiple factors related to liver fibrosis during HIV infection (Fig. 1). These include: the effects of antiretroviral therapy (ART), persistent HIV infection-induced immune activation, inflammation due to bacterial translocation from the gastrointestinal tract into the portal circulation, and insulin resistance. We also describe mechanisms related to co-infection with viral hepatitis, but we have not extended on this topic since there are multiple comprehensive reviews about this subject in the literature.11,12 Open in a separate window 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. Our search strategy included search of the PubMed database from 1980 until 2016. We used multiple search terms, including: HIV, liver fibrosis, inflammation, mitochondrial oxidation, etc. We included primarily research articles, as well as review articles for general relevant and not controversial data. Metabolic dysfunction during HIV infection Prior to the availability of effective ART, patients EPZ020411 hydrochloride with HIV infection exhibit progressive impairment of their immune systems, leading to AIDS and death. With effective ART, the development of AIDS can be prevented and people with HIV infection on successful ART have almost the same life expectancy as HIV-uninfected persons (although in countries such as the United States, these elite responders to ART represent less than 50% of the HIV population).13 As HIV-infected patients age, they develop increased abdominal obesity and exhibit an increased incidence of non-alcoholic fatty liver disease (NAFLD), with 30-40% of HIV-infected patients EPZ020411 hydrochloride showing evidence of NAFLD versus 15-20% of HIV-uninfected individuals.14,15 Moreover, a recent study shows that HIV-positive individuals with NAFLD have almost double the rates of steatohepatitis (lobular inflammation and elevated levels of aspartate aminotransferase/alanine aminotransferase) compared to age/sex-matched HIV-negative controls.16 Since excessive lipid accumulation in the liver leads to HSC activation, NAFLD and steatohepatitis enhance the risk of developing liver fibrosis. A study in a Canadian population showed that the mean BMI among HIV-infected patients with liver histology compatible with NAFLD was 26, compared to a mean BMI of 30 among non-infected patients, suggesting that HIV patients have a lower threshold for developing fatty infiltration of the liver.17 A cross-sectional study examining hepatic steatosis in HIV patients receiving ART suggested that certain medications included.