Synergy of entry inhibitors with direct-acting antivirals uncovers novel combinations for prevention and treatment of hepatitis C.
OBJECTIVE
Although direct-acting antiviral agents (DAAs) have markedly improved the outcome of treatment in chronic HCV infection, there continues to be an unmet medical need for improved therapies in difficult-to-treat patients as well as liver graft infection. Viral entry is a promising target for antiviral therapy.


METHODS
Aiming to explore the role of entry inhibitors for future clinical development, we investigated the antiviral efficacy and toxicity of entry inhibitors in combination with DAAs or other host-targeting agents (HTAs). Screening a large series of combinations of entry inhibitors with DAAs or other HTAs, we uncovered novel combinations of antivirals for prevention and treatment of HCV infection.


RESULTS
Combinations of DAAs or HTAs and entry inhibitors including CD81-, scavenger receptor class B type I (SR-BI)- or claudin-1 (CLDN1)-specific antibodies or small-molecule inhibitors erlotinib and dasatinib were characterised by a marked and synergistic inhibition of HCV infection over a broad range of concentrations with undetectable toxicity in experimental designs for prevention and treatment both in cell culture models and in human liver-chimeric uPA/SCID mice.


CONCLUSIONS
Our results provide a rationale for the development of antiviral strategies combining entry inhibitors with DAAs or HTAs by taking advantage of synergy. The uncovered combinations provide perspectives for efficient strategies to prevent liver graft infection and novel interferon-free regimens.
Inserm, U1110, Strasbourg, France Université de Strasbourg, Strasbourg, France.
Fei
F
Xiao
Inserm, U1110, Strasbourg, France Université de Strasbourg, Strasbourg, France.
Isabel
I
Fofana
Inserm, U1110, Strasbourg, France Université de Strasbourg, Strasbourg, France.
Christine
C
Thumann
Inserm, U1110, Strasbourg, France Université de Strasbourg, Strasbourg, France.
Laurent
L
Mailly
Inserm, U1110, Strasbourg, France Université de Strasbourg, Strasbourg, France Inserm, U977, Strasbourg, France.
Roxane
R
Alles
Inserm, U1110, Strasbourg, France Université de Strasbourg, Strasbourg, France.
Eric
E
Robinet
Pôle de Santé Publique, Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg, France.
Nicolas
N
Meyer
Pôle de Santé Publique, Centre Hospitalier Régional Universitaire de Strasbourg, Strasbourg, France.
Mickaël
M
Schaeffer
Inserm, U1110, Strasbourg, France Université de Strasbourg, Strasbourg, France Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
François
F
Habersetzer
Inserm, U1110, Strasbourg, France Université de Strasbourg, Strasbourg, France Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France.
Michel
M
Doffoël
Rega Institute for Medical Research, KULeuven, Leuven, Belgium.
Pieter
P
Leyssen
Rega Institute for Medical Research, KULeuven, Leuven, Belgium.
Johan
J
Neyts
Inserm, U1110, Strasbourg, France Université de Strasbourg, Strasbourg, France.
Mirjam B
MB
Zeisel
Inserm, U1110, Strasbourg, France Université de Strasbourg, Strasbourg, France Pôle Hépato-digestif, Hôpitaux Universitaires de Strasbourg, Strasbourg, France Gastrointestinal Unit, Massachusetts General Hospital, Harvard Medical School, Boston, USA.
Thomas F
TF
Baumert
D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D002460:Cell Line; D002678:Chimera; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy* / Q000517:prevention & control; D022781:Hepatocytes / Q000187:drug effects / Q000821:virology; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D053586:Virus Internalization / Q000187:drug effects*
D000998:Antiviral Agents
HCV; HEPATITIS C; LIVER