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


Autoři: Jason T. Blackard aff001;  Ling Kong aff001;  Susan D. Rouster aff001;  Rebekah Karns aff002;  Paul S. Horn aff003;  Shyam Kottilil aff005;  M. Tarek Shata aff001;  Kenneth E. Sherman aff001
Působiště autorů: Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America aff001;  Digestive Health Center, Cincinnati Children’s Hospital, Cincinnati, OH, United States of America aff002;  Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America aff003;  Neurology Division, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, United States of America aff004;  University of Maryland, Baltimore, MD, United States of America aff005
Vyšlo v časopise: PLoS ONE 14(10)
Kategorie: Research Article
doi: https://doi.org/10.1371/journal.pone.0224523

Souhrn

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.

Klíčová slova:

Hepatitis C virus – Hepatocytes – Chemokines – Small interfering RNAs – Viral replication – Virions – CCR5 coreceptor


Zdroje

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