Antiviral screening identifies adenosine analogs targeting the endogenous dsRNA Leishmania RNA virus 1 (LRV1) pathogenicity factor.

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State: Public
Version: author
Serval ID
serval:BIB_9466129FAB72
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Antiviral screening identifies adenosine analogs targeting the endogenous dsRNA Leishmania RNA virus 1 (LRV1) pathogenicity factor.
Journal
Proceedings of the National Academy of Sciences of the United States of America
Author(s)
Kuhlmann F.M., Robinson J.I., Bluemling G.R., Ronet C., Fasel N., Beverley S.M.
ISSN
1091-6490 (Electronic)
ISSN-L
0027-8424
Publication state
Published
Issued date
31/01/2017
Peer-reviewed
Oui
Volume
114
Number
5
Pages
E811-E819
Language
english
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
The endogenous double-stranded RNA (dsRNA) virus Leishmaniavirus (LRV1) has been implicated as a pathogenicity factor for leishmaniasis in rodent models and human disease, and associated with drug-treatment failures in Leishmania braziliensis and Leishmania guyanensis infections. Thus, methods targeting LRV1 could have therapeutic benefit. Here we screened a panel of antivirals for parasite and LRV1 inhibition, focusing on nucleoside analogs to capitalize on the highly active salvage pathways of Leishmania, which are purine auxotrophs. Applying a capsid flow cytometry assay, we identified two 2'-C-methyladenosine analogs showing selective inhibition of LRV1. Treatment resulted in loss of LRV1 with first-order kinetics, as expected for random virus segregation, and elimination within six cell doublings, consistent with a measured LRV1 copy number of about 15. Viral loss was specific to antiviral nucleoside treatment and not induced by growth inhibitors, in contrast to fungal dsRNA viruses. Comparisons of drug-treated LRV1 <sup>+</sup> and LRV1 <sup>-</sup> lines recapitulated LRV1-dependent pathology and parasite replication in mouse infections, and cytokine secretion in macrophage infections. Agents targeting Totiviridae have not been described previously, nor are there many examples of inhibitors acting against dsRNA viruses more generally. The compounds identified here provide a key proof-of-principle in support of further studies identifying efficacious antivirals for use in in vivo studies of LRV1-mediated virulence.

Keywords
Animals, Antiviral Agents/pharmacology, Capsid Proteins/genetics, Capsid Proteins/metabolism, Leishmania braziliensis/virology, Leishmania guyanensis/virology, Leishmaniasis/parasitology, Leishmaniavirus/drug effects, Leishmaniavirus/genetics, Leishmaniavirus/metabolism, Mice, Inbred C57BL, Nucleosides/pharmacology, Nucleotides/pharmacology, chemotherapy, endobiont virus, trypanosomatid protozoan parasite, viral segregation, virulence
Pubmed
Web of science
Open Access
Yes
Create date
24/01/2017 14:59
Last modification date
20/08/2019 15:57
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