Vps4 and the ESCRT-III complex are required for the release of infectious hepatitis C virus particles

Lynsey Corless1, Colin M Crump, Stephen D C Griffin

  • 1Institute of Molecular and Cellular Biology and Astbury Centre for Structural Molecular Biology, University of Leeds, Leeds LS2 9JT, West Yorkshire, UK.

Insights

Hepatitis C virus (HCV) release depends on the endosomal sorting complex required for transport (ESCRT) pathway. Late ESCRT-III and Vps4 components are crucial for infectious HCV particle production and release from cells.

Area of Science:

  • Virology
  • Cell Biology
  • Molecular Biology

Background:

  • Hepatitis C virus (HCV) assembly and release mechanisms are not fully understood.
  • Enveloped viruses like HIV-1 use the host's endosomal sorting complex required for transport (ESCRT) machinery for particle formation and release.
  • The role of the ESCRT pathway in HCV egress remains to be elucidated.

Purpose of the Study:

  • To investigate whether the ESCRT pathway is involved in the release of infectious Hepatitis C virus (HCV) particles.
  • To determine which specific components of the ESCRT pathway are essential for HCV egress.

Main Methods:

  • Established a conditional virus-like particle (VLP) assembly system using trans-complementation of an envelope-deleted JFH-1 genome.
  • Utilized dominant-negative mutants of ESCRT-III components and Vps4 to inhibit ESCRT pathway function.
  • Assessed the impact of ESCRT inhibition on infectious particle production, virus genome replication, and intracellular infectious particle accumulation using focus-forming assays.

Main Results:

  • Inhibition of late ESCRT-III components or Vps4 significantly reduced the production of infectious HCV particles.
  • Dominant-negative ESCRT-I or Alix did not affect HCV particle release.
  • ESCRT inhibition did not impact HCV genome replication or the accumulation of intracellular infectious particles, indicating a specific role in release.

Conclusions:

  • HCV requires late components of the ESCRT pathway, specifically ESCRT-III and Vps4, for the efficient release of infectious virus particles.
  • The ESCRT pathway plays a critical role in the egress of Hepatitis C virus from infected host cells.

Related Concept Videos

Hepatitis01:25

Hepatitis

Hepatitis is an inflammatory condition of the liver most commonly caused by hepatotropic viruses (A–E), though non-infectious causes such as alcohol and drugs also exist.Hepatitis AHepatitis A virus (HAV) is a non-enveloped RNA virus of the Picornaviridae family. It is primarily transmitted via the fecal-oral route, typically through ingestion of contaminated food or water. After ingestion, HAV enters the bloodstream through the oropharynx or intestinal epithelium and reaches the liver. The...
Intralumenal Vesicles and Multivesicular Bodies01:38

Intralumenal Vesicles and Multivesicular Bodies

Intraluminal vesicles (ILVs) are small vesicles 50-80 nm in diameter formed during the maturation of early endosomes. A specialized endosome containing numerous ILVs is called a multivesicular body (MVB). ILVs contain internalized molecules such as antigens, nucleic acids, proteins, and metabolites. Some of these molecules are released from the MVBs inside exosomes and are transported to other cells. Other MVBs contain molecules that are retained in the ILVs and are later degraded within the...
Inhibitors Of Virion Release01:25

Inhibitors Of Virion Release

Viral replication and dissemination rely on efficient mechanisms for host cell entry, genome replication, assembly, and release. Influenza viruses, such as types A and B, are negative-sense single-stranded RNA viruses with a segmented genome, that depend on two critical surface glycoproteins to carry out these processes: hemagglutinin (HA) and neuraminidase (NA). HA initiates infection by binding to sialic acid residues on the surface of host epithelial cells, facilitating receptor-mediated...
Viral Hepatitis I: Introduction01:28

Viral Hepatitis I: Introduction

Viral hepatitis is an inflammatory condition of the liver caused by infection with hepatotropic viruses, most commonly hepatitis A, B, C, D, and E. Despite variations in structure and transmission, all viruses mentioned infect hepatocytes and provoke immune responses that can hinder liver function. Additionally, some non-hepatotropic viruses can also lead to hepatic inflammation.Hepatitis A VirusHepatitis A virus (HAV) is transmitted through the fecal–oral route, typically by ingestion of food...
Inhibitors of Virion Maturation and Assembly01:19

Inhibitors of Virion Maturation and Assembly

As part of their replication cycle, certain viruses synthesize long precursor proteins called polyproteins within infected host cells. In human immunodeficiency virus (HIV), two major polyproteins are produced: Gag and Gag-Pol. The Gag polyprotein supplies the structural components of the virus, while Gag-Pol includes essential viral enzymes such as reverse transcriptase, integrase, and protease. After synthesis, these polyproteins move to the host cell membrane, where they assemble into an...
Retrovirus Life Cycles01:10

Retrovirus Life Cycles

Retroviruses have a single-stranded RNA genome that undergoes a special form of replication. Once the retrovirus has entered the host cell, an enzyme called reverse transcriptase synthesizes double-stranded DNA from the retroviral RNA genome. This DNA copy of the genome is then integrated into the host’s genome inside the nucleus via an enzyme called integrase. Consequently, the retroviral genome is transcribed into RNA whenever the host’s genome is transcribed, allowing the retrovirus to...