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PLoS One. 2019 Oct 29;14(10):e0224523. doi: 10.1371/journal.pone.0224523. eCollection 2019.

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

Author information

1
Division of Digestive Diseases, Department of Internal Medicine, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.
2
Digestive Health Center, Cincinnati Children's Hospital, Cincinnati, OH, United States of America.
3
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, United States of America.
4
Neurology Division, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States of America.
5
University of Maryland, Baltimore, MD, United States of America.

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.

Conflict of interest statement

Dr Sherman has received research grants or contracts awarded to his institution from AbbVie, Gilead Sciences, Inc, Merck, Intercept Pharmaceuticals, Inc, and Inovio. He has served as an advisory board member or a consultant to Abbott Laboratories and uniQure. He has also served on data and safety monitoring boards for Watermark (Allergan) and MedPace. This does not alter our adherence to PLOS ONE policies on sharing data and materials. All other authors have nothing to disclose.

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