Abstract:
BACKGROUND & AIMS:Hepatitis C virus (HCV) evades humoral immunity and establishes chronic infections. Virus particles circulate in complex with lipoproteins facilitating antibody escape. Apolipoprotein E (ApoE) is essential for intracellular HCV assembly and for HCV cell entry. We aimed to explore if ApoE released from non-infected cells interacts with and modulates secreted HCV particles. METHODS:ApoE secreted from non-infected cells was incubated with HCV from primary human hepatocytes or Huh-7.5 cells. Co-immunoprecipitation, viral infectivity and neutralization experiments were conducted. RESULTS:Physiological levels of secreted ApoE (10-60µg/ml) enhanced the infectivity of HCV up to 8-fold across all genotypes, which indirectly decreased virus neutralization by antibodies targeting E1 or E2 up to 10-fold. Infection enhancement was observed for particles produced in primary human hepatocytes and Huh-7.5 cells. Selective depletion of ApoE ablated infection enhancement. Addition of HA-tagged ApoE to HCV particles permitted co-precipitation of HCV virions. Serum ApoE levels ranged between 10-60µg/ml, which is ca 100-fold higher than in Huh-7.5 conditioned cell culture fluids. Serum-derived HCV particles carried much higher amounts of ApoE than cell culture-derived HCV particles. Serum ApoE levels correlated with efficiency of co-precipitation of HCV upon exogenous addition of HA-ApoE. ApoE-dependent infection enhancement was independent of the hypervariable region 1 and SR-B1, but was dependent on heparan sulfate proteoglycans (HSPGs). CONCLUSIONS:Physiological quantities of secreted ApoE stimulate HCV infection and increase antibody escape, by incorporating into virus particles and enhancing particle interactions with cellular HSPGs. Thus, secreted particles undergo ApoE-dependent maturation to enhance infectivity and to facilitate evasion from neutralizing antibodies. Lay summary: This study shows that HCV particle infectivity is remodeled by secreted ApoE after particle release from cells. Fluctuation of the availability of ApoE likely influences HCV infectivity, antibody escape and transmission.
journal_name
J Hepatoljournal_title
Journal of hepatologyauthors
Bankwitz D,Doepke M,Hueging K,Weller R,Bruening J,Behrendt P,Lee JY,Vondran FWR,Manns MP,Bartenschlager R,Pietschmann Tdoi
10.1016/j.jhep.2017.04.010subject
Has Abstractpub_date
2017-09-01 00:00:00pages
480-489issue
3eissn
0168-8278issn
1600-0641pii
S0168-8278(17)30251-9journal_volume
67pub_type
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更新日期:1999-02-01 00:00:00
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更新日期:2002-03-01 00:00:00
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pub_type: 杂志文章
doi:10.1016/s0168-8278(01)00042-3
更新日期:2001-06-01 00:00:00
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pub_type: 临床试验,杂志文章,多中心研究
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更新日期:2017-03-01 00:00:00
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pub_type: 临床试验,杂志文章,随机对照试验
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更新日期:1996-01-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 临床试验,杂志文章,随机对照试验
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journal_title:Journal of hepatology
pub_type: 杂志文章,评审
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journal_title:Journal of hepatology
pub_type: 杂志文章
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journal_title:Journal of hepatology
pub_type: 杂志文章,评审
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journal_title:Journal of hepatology
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更新日期:2019-04-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:1995-07-01 00:00:00
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journal_title:Journal of hepatology
pub_type: 杂志文章
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更新日期:1996-06-01 00:00:00