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    CCR5 receptor antagonism inhibits hepatitis C virus (HCV) replication in vitro.

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    Author
    Blackard, Jason T
    Kong, Ling
    Kottilil, Shyam
    Date
    2019-10-29
    Journal
    PLoS One
    Publisher
    Public Library of Science
    Type
    Article
    
    Metadata
    Show full item record
    See at
    https://doi.org/10.1371/journal.pone.0224523
    Abstract
    Background and aim The hepatitis C virus (HCV) is a single-strand RNA virus that infects millions of people worldwide. Recent advances in therapy have led to viral cure using two- and three- drug combinations of direct acting inhibitors of viral replication. CCR5 is a chemokine receptor that is expressed on hepatocytes and represents a key co-receptor for HIV. We evaluated the effect of CCR5 blockade or knockdown on HCV replication in Huh7.5JFH1 cells. Methods Cells were exposed to varying concentrations of maraviroc (CCR5 inhibitor), cenicriviroc (CCR2/CCR5 inhibitor), sofosbuvir (nucleotide polymerase inhibitor), or raltegravir (HIV integrase inhibitor). Results HCV RNA was detected utilizing two qualitative strand-specific RT-PCR assays. HCV core antigen and NS3 protein was quantified in the supernatant and cell lysate, respectively. siRNA was utilized to knockdown CCR5 gene expression in hepatocytes. Alternatively, anti-CCR5 antibodies were employed to block the receptor. Supernatant levels of HCV RNA (expressed as fold change) were not reduced in the presence of raltegravir but were reduced 8.55-fold and 12.42-fold with cenicriviroc and maraviroc, respectively. Sofosbuvir resulted in a 16.20-fold change in HCV RNA levels. HCV core and NS3 protein production was also reduced in a dose-dependent manner. Two distinct anti-CCR5 antibodies also resulted in a significant reduction in HCV protein expression, as did siRNA knockdown of CCR5 gene expression. Conclusions These data provide evidence that CCR5 modulation could have a significant effect on HCV replication in an in vitro system. Further evaluation of the role of CCR5 inhibition in clinical settings may be warranted.
    Sponsors
    This work was supported in part by grant NIAID R01AI065256 to KES. (https://www.niaid. nih.gov/).
    Keyword
    Receptors, CCR5
    CCR5 Receptor Antagonists
    Hepatitis C
    RNA, Small Interfering
    In Vitro Techniques
    Identifier to cite or link to this item
    http://hdl.handle.net/10713/11245
    ae974a485f413a2113503eed53cd6c53
    10.1371/journal.pone.0224523
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