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

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 hepatocyte...

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Bibliographic Details
Published in:PloS one 2019-10, Vol.14 (10), p.e0224523-e0224523
Main Authors: Blackard, Jason T, Kong, Ling, Rouster, Susan D, Karns, Rebekah, Horn, Paul S, Kottilil, Shyam, Shata, M Tarek, Sherman, Kenneth E
Format: Article
Language:English
Subjects:
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
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Summary: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.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0224523