Journal Article

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

Shata, M. Tarek, Karns, Rebekah, Horn, Paul S., Kong, Ling, Rouster, Susan D., Blackard, Jason T., Kottilil, Shyam, Sherman, Kenneth E.

2019

Overview

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. Cells were exposed to varying concentrations of maraviroc (CCR5 inhibitor), cenicriviroc (CCR2/CCR5 inhibitor), sofosbuvir (nucleotide polymerase inhibitor), or raltegravir (HIV integrase inhibitor). 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. 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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Acquired immune deficiency syndrome / AIDS / Antibodies / Antigens / Antiretroviral agents / Biology and Life Sciences / Care and treatment / CC chemokine receptors / CCR2 protein / CCR5 protein / CCR5 Receptor Antagonists - metabolism / Cell culture / Cell Line / Chemokines / Combination drug therapy / Core protein / Dosage and administration / Gene expression / Genes / Hepacivirus - genetics / Hepacivirus - metabolism / Hepacivirus - pathogenicity / Hepatitis / Hepatitis C / Hepatitis C - drug therapy / Hepatitis C - virology / Hepatitis C virus / Hepatocytes / HIV / HIV infections / Human immunodeficiency virus / Humans / Imidazoles - therapeutic use / Immunoglobulins / Infections / Inhibitors / Integrase / Internal medicine / Lipids / Maraviroc / Maraviroc - therapeutic use / Medical schools / Medicine / Medicine and Health Sciences / Monocyte chemoattractant protein 1 / Mutation / NS3 protein / Nucleotides / Polymerase chain reaction / Protein folding / Proteins / Raltegravir / Raltegravir Potassium - therapeutic use / Receptors, CCR5 - metabolism / Replication / Ribonucleic acid / RNA / RNA polymerase / RNA viruses / siRNA / Sofosbuvir / Sofosbuvir - therapeutic use / Sulfoxides / Viral infections / Virology / Virus replication / Virus Replication - drug effects / Viruses