1 Centre de Recherche du CHUM (CRCHUM) et Faculté de Médecine, Université de Montréal, Montréal, Canada.
2 Pharmacology Department, Medical Research Division, National Research Centre, Cairo, Egypt.
3 Institut National de la Recherche Scientifique, Centre Armand-Frappier Santé Biotechnologie, Université du Québec, Laval, Canada.
4 Centre de recherche du CHU de Québec et Faculté de médecine, Université Laval, Québec, Canada.
5 Concordia University, Montréal, Canada.
6 Centre de Recherche du CHUM (CRCHUM) et Faculté de Médecine, Université de Montréal, Montréal, Canada. daniel.lamarre@umontreal.ca.
7 Department of Pathology, Case Western Reserve University, 2103 Cornell Road, Cleveland, Ohio, 44106, USA. daniel.lamarre@umontreal.ca.

Flaviviridae infections represent a major global health burden. By deciphering mechanistic aspects of hepatitis C virus (HCV)-host interactions, one could discover common strategy for inhibiting the replication of related flaviviruses. By elucidating the HCV interactome, we identified the 17-beta-hydroxysteroid dehydrogenase type 12 (HSD17B12) as a human hub of the very-long-chain fatty acid (VLCFA) synthesis pathway and core interactor. Here we show that HSD17B12 knockdown (KD) impairs HCV replication and reduces virion production. Mechanistically, depletion of HSD17B12 induces alterations in VLCFA-containing lipid species and a drastic reduction of lipid droplets (LDs) that play a critical role in virus assembly. Oleic acid supplementation rescues viral RNA replication and production of infectious particles in HSD17B12 depleted cells, supporting a specific role of VLCFA in HCV life cycle. Furthermore, the small-molecule HSD17B12 inhibitor, INH-12, significantly reduces replication and infectious particle production of HCV as well as dengue virus and Zika virus revealing a conserved requirement across Flaviviridae virus family. Overall, the data provide a strong rationale for the advanced evaluation of HSD17B12 inhibition as a promising broad-spectrum antiviral strategy for the treatment of Flaviviridae infections.

PMID: 32132633 [PubMed - indexed for MEDLINE]