Fatty acid beta oxidation as a target for antiviral therapy against Junín virus

CECILIA A. VÁZQUEZ; CYBELE C. GARCÍA; SANDRA M. CORDO

Evento virtual

Conferencia; 34th International Conference on Antiviral Research (ICAR); 2021

International Society for Antiviral Research

Argentine Hemorrhagic Fever (AHF) is a disease caused by a member of the Arenaviridae family, Junín virus (JUNV). There is currently no chemotherapy against it, only immunotherapy with convalescent plasma. We have previouslydescribed a close relation between JUNV?s replication cycle and the host cell?s lipid metabolism. We found that cells infected with JUNV have fewer lipid droplets than non-infected cells. The activation of pro-viral autophagyafter JUNV infection could be the mechanism behind this phenotype. Since this mechanism is accompanied by an increase in fatty acid beta oxidation, we hypothesized that the latter could be targeted to inhibit JUNV?s replication.To that end, we assayed the effect on viral replication of etomoxir, a specific and irreversible inhibitor of the carnitine palmitoyltransferase I (CPT-I), a mitochondrial enzyme that catalyzes the rate limiting step in long-chain fatty acid oxidation.To test our hypothesis, we infected human hepatoma cells, HepG2 with JUNV and treated the monolayers with 5 to 200 uM of etomoxir. 48 hours post infection, the supernatants were titrated by plaque assay. The number of infective particles produced by the cells was reduced in a dose-dependent manner, reaching an EC50 of 7.7 uM, with a CC50 of 148.2 uM and an SI of 19.2. We are currently exploring this finding in depth, via RT-PCR and immunofluorescence.These results show for the first time that fatty acid beta oxidation is a pathway that could be targeted by an antiviral therapy against JUNV. Consequently, etomoxir and other inhibitors should be further studied.