Hepatitis C virus utilizes VLDLR as a novel entry pathway

Saneyuki Ujinoa, Hironori Nishitsujia, Takayuki Hishikib, Kazuo Sugiyamac, Hiroshi Takakud, and Kunitada Shimotohnoa

PNAS. 2016 vol.113(1):188-93.

Speaker: Hsin-Hsin Chen (陳亲亲)                              Time: 13:10~14:00, Mar. 23, 2016

Commentator: Dr. Kung-Chia Young (楊孔嘉老師)   Place: Room 601

Abstract:

HCV is a small, enveloped, single-stranded, positive-sense RNA virus belonging to the family Flaviviridae. HCV entry into the host cells involves various host factors that function as receptors and mediate endocytosis, which includes CD81, claudin-1 (CLDN1), occludin (OCLN), and scavenger receptor class B member I (SR-BI) and CD81 plays an important role in this process. Recent studies have demonstrated that HCV RNA replication in Huh7.5 cells is enhanced under hypoxic conditions [1], and the oxygen content in liver tissue in vivo is estimated to be lower, varying HCV life cycle significantly from that observed using in vitro culture systems. The HCV particle is a lipo-viro-particle (LPV) that contains apolipoprotein B-100 (ApoB) and ApoE (19, 20). In addition the very-low-density lipoprotein receptor (VLDLR) can be induced under hypoxic conditions. Hence, the author has hypothesized that the HCV life cycle might be influenced by oxygen levels. Here, the author found that HCV entry significantly increased in VLDLR up-regulated Huh7.5 cells under hypoxic conditions whereas no such effect was observed in the cells grown under normoxicconditions. The author did not find any difference in the level of HCV RNA and proteins in HCV full-length RNA replicon cells. Further, they found that the HCV infection is reduced by antibodies against ApoE and HCV E2 in Huh7.5 cells and in VLDLR dependent expressed Huh7 cells, suggesting that ApoE and HCV E2 mediate VLDLR HCV entry. Moreover, knockdown of the factors CLDN1, OCLN, SR-BI, LDLR, or Niemann-Pic C1-like 1 (NPC1L1) did not suppress Luc-HCVccJFH1 entry into VLDLR-expressing Huh7.5 and CD81-deficient Huh7.5 cells. Importantly, VLDLR mRNA and protein expression were observed in human liver tissue and primary human hepatocytes(PHHs). In conclusion, VLDLR functions as an HCV receptor in vivo independent of canonical CD81-mediated HCV entry.

References:

1.         Vassilaki N, et al. (2013) Low oxygen tension enhances hepatitis C virus replication. J Virol 87(5):2935–2948.

2.         Nielsen SU, et al. (2006) Association between hepatitis C virus and very-low-density lipoprotein (VLDL)/LDL analyzed in iodixanol density gradients. J Virol 80(5): 2418–2428.