[Source: PLoS Neglected Tropical Diseases, full page: (LINK). Abstract, edited.]
OPEN ACCESS / PEER-REVIEWED / RESEARCH ARTICLE
Yellow fever virus is susceptible to sofosbuvir both in vitroand in vivo
Caroline S. de Freitas , Luiza M. Higa , Carolina Q. Sacramento, André C. Ferreira, Patrícia A. Reis, Rodrigo Delvecchio, Fabio L. Monteiro, Giselle Barbosa-Lima, Harrison James Westgarth, Yasmine Rangel Vieira, Mayara Mattos, Natasha Rocha, Lucas Villas Bôas Hoelz, [ … ], Thiago Moreno L. Souza
Published: January 30, 2019 / DOI: https://doi.org/10.1371/journal.pntd.0007072 / This is an uncorrected proof.
Yellow fever virus (YFV) is a member of the Flaviviridae family. In Brazil, yellow fever (YF) cases have increased dramatically in sylvatic areas neighboring urban zones in the last few years. Because of the high lethality rates associated with infection and absence of any antiviral treatments, it is essential to identify therapeutic options to respond to YFV outbreaks. Repurposing of clinically approved drugs represents the fastest alternative to discover antivirals for public health emergencies. Other Flaviviruses, such as Zika (ZIKV) and dengue (DENV) viruses, are susceptible to sofosbuvir, a clinically approved drug against hepatitis C virus (HCV). Our data showed that sofosbuvir docks onto YFV RNA polymerase using conserved amino acid residues for nucleotide binding. This drug inhibited the replication of both vaccine and wild-type strains of YFV on human hepatoma cells, with EC50 values around 5 μM. Sofosbuvir protected YFV-infected neonatal Swiss mice and adult type I interferon receptor knockout mice (A129-/-) from mortality and weight loss. Because of its safety profile in humans and significant antiviral effects in vitro and in mice, Sofosbuvir may represent a novel therapeutic option for the treatment of YF.
Key-words: Yellow fever virus; Yellow fever, antiviral; sofosbuvir
Yellow fever virus is transmitted by mosquitoes and its infection may be asymptomatic or lead to a wide clinical spectrum ranging from a mild febrile illness to a potentially lethal viral hemorrhagic fever characterized by liver damage. Although a yellow fever vaccine is available, low coverage allows 80,000–200,000 cases and 30,000–60,000 deaths annually worldwide. There are no specific therapy and treatment relies on supportive care, reinforcing an urgent need for antiviral repourposing. Here, we showed that sofosbuvir, clinically approved against hepatitis C, inhibits yellow fever virus replication in liver cell lines and animal models. In vitro, sofosbuvir inhibits viral RNA replication, decreases the number of infected cells and the production of infectious virus particles. These data is particularly relevante since the liver is the main target of yellow fever infection. Sofosbuvir also protected infected animals from mortality, weight loss and liver injury, especially prophylatically. Our pre-clinical results supports a second use of sofosbuvir against yellow fever.
Citation: de Freitas CS, Higa LM, Sacramento CQ, Ferreira AC, Reis PA, Delvecchio R, et al. (2019) Yellow fever virus is susceptible to sofosbuvir both in vitro and in vivo. PLoS Negl Trop Dis 13(1): e0007072. https://doi.org/10.1371/journal.pntd.0007072
Editor: Samuel V. Scarpino, Northeastern University, UNITED STATES
Received: March 25, 2018; Accepted: December 12, 2018; Published: January 30, 2019
Copyright: © 2019 de Freitas et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Data Availability: All relevant data are within the paper and its Supporting Information files.
Funding: The financial support was provided by Fundação de Amparo à Pesquisa do Estado do Rio de Janeiro (FAPERJ – http://www.faperj.br/ – Grant Number E-26/201.573/2014) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq – http://cnpq.br/ – Grant Numbers 306389/2014-2 and 425636/2016-0). TMLS received the funds. This work has received financial support from the National Institute of Science and Technology in Dengue (INCT dengue), a scheme funded by the Brazilian National Science Council (CNPq, Brazil) and Minas Gerais Foundation for Science (FAPEMIG, Brazil). Funding was also provided by National Council for Scientific and Technological Development (CNPq), Ministry of Science, Technology, Information and Communications (no. 465313/2014-0); Ministry of Education/CAPES (no. 465313/2014-0); Research Foundation of the State of Rio de Janeiro/FAPERJ (no. 465313/2014-0) and Oswaldo Cruz Foundation/FIOCRUZ to National Institute for Science and Technology on Innovation on Diseases of Neglected Populations (INCT/IDPN), Center for Technological Development in Health (CDTS), Fiocruz, Rio de Janeiro, RJ, Brazil. This study was financed in part by the Coordenação de Aperfeiçoamento de Pessoal de Nível Superior – Brasil (CAPES) – Finance Code 001. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have declared that no competing interests exist.
Keywords: Yellow Fever; Flavivirus; Antivirals; Sofosbuvir; Animal models.