Apolipoprotein E, but Not Apolipoprotein B, Is Essential for Efficient Cell-to-Cell Transmission of Hepatitis C Virus

• Published in: Journal of virology Vol. 89; no. 19; pp. 9962 - 9973
• Main Authors: Gondar, Virgínia, Molina-Jiménez, Francisca, Hishiki, Takayuki, García-Buey, Luisa, Koutsoudakis, George, Shimotohno, Kunitada, Benedicto, Ignacio, Majano, Pedro L
• Format: Journal Article
• Language: English
• Published: United States American Society for Microbiology 01-10-2015
• Subjects: Apolipoproteins B - antagonists & inhibitors; Apolipoproteins B - genetics; Apolipoproteins B - metabolism; Apolipoproteins E - antagonists & inhibitors; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Cell Line; Cell-Free System; Gene Knockdown Techniques; Hepacivirus - genetics; Hepacivirus - pathogenicity; Hepacivirus - physiology; Hepatitis C - metabolism; Hepatitis C - transmission; Hepatitis C - virology; Hepatitis C virus; Hepatocytes - metabolism; Hepatocytes - virology; Host-Pathogen Interactions - physiology; Humans; Lipoproteins, VLDL - metabolism; Models, Biological; Virus Assembly - physiology; Virus-Cell Interactions
• ISSN: 0022-538X; 1098-5514
• DOI: 10.1128/JVI.00577-15

Hepatitis C virus (HCV) infects hepatocytes through two different routes: (i) cell-free particle diffusion followed by engagement with specific cellular receptors and (ii) cell-to-cell direct transmission mediated by mechanisms not well defined yet. HCV exits host cells in association with very-low-density lipoprotein (VLDL) components. VLDL particles contain apolipoproteins B (ApoB) and E (ApoE), which are required for viral assembly and/or infectivity. Based on these precedents, we decided to study whether these VLDL components participate in HCV cell-to-cell transmission in vitro. We observed that cell-to-cell viral spread was compromised after ApoE interference in donor but not in acceptor cells. In contrast, ApoB knockdown in either donor or acceptor cells did not impair cell-to-cell viral transmission. Interestingly, ApoB participated in the assembly of cell-free infective virions, suggesting a differential regulation of cell-to-cell and cell-free HCV infection. This study identifies host-specific factors involved in these distinct routes of infection that may unveil new therapeutic targets and advance our understanding of HCV pathogenesis.
This work demonstrates that cell-to-cell transmission of HCV depends on ApoE but not ApoB. The data also indicate that ApoB is required for the assembly of cell-free infective particles, strongly suggesting the existence of mechanisms involving VLDL components that differentially regulate cell-free and cell-to-cell HCV transmission. These data clarify some of the questions regarding the role of VLDL in HCV pathogenesis and the transmission of the virus cell to cell as a possible mechanism of immune evasion and open the door to therapeutic intervention.