title: Dengue Virus Evolution under a Host-Targeted Antiviral.
abstract: The host-targeted antiviral drug UV-4B reduces viral replication and promotes survival in a mouse model of experimental dengue virus (DENV) infection. UV-4B is an iminosugar that inhibits the α-glucosidase family of enzymes and subsequently the folding of glycosylated proteins, both viral and host. Here, we utilized next-generation sequencing to investigate evolution of a flavivirus under selective pressure by a host-targeted antiviral in vivo. In viral populations recovered from UV-4B-treated mice, there was a significant increase in the number of single-nucleotide polymorphisms (SNPs) and the ratio of nonsynonymous to synonymous SNPs compared to findings in viral populations from vehicle-treated mice. The strongest evidence of positive selection was in the glycosylated membrane protein, thereby providing in vivo validation of the mechanism of action of an iminosugar. In addition, mutations in glycosylated proteins were present only in drug-treated mice after a single passage. However, the bulk of the other mutations were present in both populations, indicating nonspecific selective pressure. Together with the continued control of viremia by UV-4B, these findings are consistent with the previously predicted high genetic barrier to escape mutations in host-targeted antivirals.
  
  
  OBJECTIVE
  Although hundreds of millions of people are infected with DENV every year, there is currently no approved vaccine or antiviral therapy. UV-4B has demonstrated antiviral activity against DENV and is expected to enter clinical trials soon. Therefore, it is important to understand the mechanisms of DENV resistance to UV-4B. Host-targeted antivirals are thought to have a higher genetic barrier to escape mutants than directly acting antivirals, yet there are very few published studies of viral evolution under host-targeted antivirals. No study to date has described flavivirus evolution in vivo under selective pressure by a host-based antiviral drug. We present the first in vivo study of the sequential progression of viral evolution under selective pressure by a host-targeted antiviral compound. This study bolsters support for the clinical development of UV-4B as an antiviral drug against DENV, and it provides a framework to compare how treatment with other host-targeted antiflaviviral drugs in humans and different animal models influence viral genetic diversity.
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Emily
authors.initials: E
authors.lastname: Plummer
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Buck
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Marisa
authors.initials: M
authors.lastname: Sanchez
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Jason A
authors.initials: JA
authors.lastname: Greenbaum
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Julia
authors.initials: J
authors.lastname: Turner
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Rajvir
authors.initials: R
authors.lastname: Grewal
authors.affiliation: Unither Virology, LLC, Silver Spring, Maryland, USA.
authors.forename: Brennan
authors.initials: B
authors.lastname: Klose
authors.affiliation: Unither Virology, LLC, Silver Spring, Maryland, USA.
authors.forename: Aruna
authors.initials: A
authors.lastname: Sampath
authors.affiliation: Unither Virology, LLC, Silver Spring, Maryland, USA.
authors.forename: Kelly L
authors.initials: KL
authors.lastname: Warfield
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: Bjoern
authors.initials: B
authors.lastname: Peters
authors.affiliation: Unither Virology, LLC, Silver Spring, Maryland, USA.
authors.forename: Urban
authors.initials: U
authors.lastname: Ramstedt
authors.affiliation: La Jolla Institute for Allergy and Immunology, La Jolla, California, USA sujan@lji.org.
authors.forename: Sujan
authors.initials: S
authors.lastname: Shresta
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D003715:Dengue / Q000188:drug therapy* / Q000821:virology*; D003716:Dengue Virus / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D004195:Disease Models, Animal; D019143:Evolution, Molecular; D014644:Genetic Variation; D054884:Host-Pathogen Interactions / Q000187:drug effects; D006801:Humans; D050111:Imino Sugars / Q000494:pharmacology; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012641:Selection, Genetic; D014764:Viral Proteins / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D050111:Imino Sugars; D014764:Viral Proteins