Elucidating the role of extracellular vesicles in liver injury induced by HIV

ABSTRACT

Introduction

Liver disease is known as one of the leading co-morbidities in HIV infection, with 18% of non-AIDS-related mortality. There is constant crosstalk between liver parenchymal (hepatocytes) and non-parenchymal cells (macrophages, hepatic stellate cells, endothelial cells), and extracellular vesicles (EVs) are one of the most important ways of cell-to-cell communication.

Areas covered

We briefly cover the role of EVs in liver disease as well as what is known about the role of small EVs, exosomes, in HIV-induced liver disease potentiated by alcohol as one of the second hits. We also touch large EVs, apoptotic bodies (ABs), in HIV-induced liver injury, the mechanisms of their formation and potentiation by second hits, and their role in the progression of liver disease.

Expert Opinion/Commentary

Liver cells are an important source of EVs, which may provide the connection between different organs via secretion into the circulating blood (exosomes) or serve for the communication between the cells within the organ (ABs). Understanding the role of liver EVs in HIV infection and the involvement of second hits in EV generation would provide a new angle for the analysis of HIV-related liver disease pathogenesis and progression to end-stage liver disease.

Plain Language Summary

People living with HIV-1 (PLWH) are at risk of developing chronic liver disease. They are often coinfected with hepatitis viruses B and C and misuse alcohol. Combining these ‘second hits’ factors with HIV infection greatly accelerates liver damage. The exact mechanisms are not clear.

• The liver contains different types of cells. Most are hepatocytes, which cannot replicate HIV but can be stressed by HIV and alcohol metabolites. During this process, hepatocytes release small extracellular vesicles called exosomes.

• Liver exosomes can carry toxic viral proteins and nucleic acids. When hepatocyte exosomes are captured by other liver cells, such as stellate cells, Kupffer macrophages, and sinusoidal endothelial cells, they change the functions of these cells.

• If hepatocytes die due to high HIV and alcohol toxicity, they form large particles called apoptotic bodies.

• Like exosomes, these large apoptotic bodies also change the functions of neighboring cells they capture.

• Macrophages and stellate cells exposed to – extracellular vesicles containing HIV proteins and nucleic acids promote liver inflammation and fibrosis.

KEYWORDS:

• HIV
• extracellular vesicles
• liver
• alcohol
• exosomes
• apoptotic bodies

Article highlights

• Liver disease is an important co-morbidity in HIV infection

• Liver damage is potentiated by second hits, like co-infections and alcohol

• Liver fibrosis is a frequent outcome of HIV-induced liver injury, especially when it is potentiated by second hits

• Extracellular vesicles (EVs) serve for cell-to-cell communications in the liver and outside the organ; they contain regulatory miRNAs which affect cell function

• Low or moderate HIV-induced oxidative stress in hepatocytes stimulate exosome release, while high oxidative stress (HIV + alcohol) induces apoptotic bodies (ABs)

• Small EVs, exosomes, released from HIV- and HIV + alcohol-exposed hepatocytes promote inflammation and liver fibrosis development

• Large EVs, ABs generated from apoptotic hepatocytes induce inflammasome when they are engulfed by macrophages

• Engulfment of HIV-containing hepatocyte ABs induces pro-fibrotic activation of hepatic stellate cells (HSC)

• Internalization of ABs generated from hepatocytes, but not from lymphocyteby HSC initiate liver fibrosis progression.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was funded by the National Institute on Alcohol Abuse and Alcoholism Under 5R01AA027189-05 (to NAO and LYP)