tetano
Editor, Senior Moderator
Sci Rep. 2019 May 16;9(1):7484. doi: 10.1038/s41598-019-43030-y.
[h=1]Lack of selective resistance of influenza A virus in presence of host-targeted antiviral, UV-4B.[/h] Warfield KL[SUP]1[/SUP], Schaaf KR[SUP]2[/SUP], DeWald LE[SUP]3[/SUP], Spurgers KB[SUP]3[/SUP], Wang W[SUP]4,[/SUP][SUP]5[/SUP], Stavale E[SUP]6,[/SUP][SUP]7[/SUP], Mendenhall M[SUP]8[/SUP], Shilts MH[SUP]2,[/SUP][SUP]4[/SUP], Stockwell TB[SUP]4,[/SUP][SUP]9[/SUP], Barnard DL[SUP]8[/SUP], Ramstedt U[SUP]10,[/SUP][SUP]7[/SUP], Das SR[SUP]11,[/SUP][SUP]12[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Development of antiviral drug resistance is a continuous concern for viruses with high mutation rates such as influenza. The use of antiviral drugs targeting host proteins required for viral replication is less likely to result in the selection of resistant viruses than treating with direct-acting antivirals. The iminosugar UV-4B is a host-targeted glucomimetic that inhibits endoplasmic reticulum α-glucosidase I and II enzymes resulting in improper glycosylation and misfolding of viral glycoproteins. UV-4B has broad-spectrum antiviral activity against diverse viruses including dengue and influenza. To examine the ability of influenza virus to develop resistance against UV-4B, mouse-adapted influenza virus was passaged in mice in the presence or absence of UV-4B and virus isolated from lungs was used to infect the next cohort of mice, for five successive passages. Deep sequencing was performed to identify changes in the viral genome during passaging in the presence or absence of UV-4B. Relatively few minor variants were identified within each virus and the ratio of nonsynonymous to synonymous (dN/dS) substitutions of minor variants confirmed no apparent positive selection following sustained exposure to UV-4B. Three substitutions (one synonymous in PB2, one nonsynonymous in M and PA each) were specifically enriched (>3%) in UV-4B-treated groups at passage five. Recombinant viruses containing each individual or combinations of these nonsynonymous mutations remained sensitive to UV-4B treatment in mice. Overall, these data provide evidence that there is a high genetic barrier to the generation and selection of escape mutants following exposure to host-targeted iminosugar antivirals.
PMID: 31097731 DOI: 10.1038/s41598-019-43030-y
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[h=1]Lack of selective resistance of influenza A virus in presence of host-targeted antiviral, UV-4B.[/h] Warfield KL[SUP]1[/SUP], Schaaf KR[SUP]2[/SUP], DeWald LE[SUP]3[/SUP], Spurgers KB[SUP]3[/SUP], Wang W[SUP]4,[/SUP][SUP]5[/SUP], Stavale E[SUP]6,[/SUP][SUP]7[/SUP], Mendenhall M[SUP]8[/SUP], Shilts MH[SUP]2,[/SUP][SUP]4[/SUP], Stockwell TB[SUP]4,[/SUP][SUP]9[/SUP], Barnard DL[SUP]8[/SUP], Ramstedt U[SUP]10,[/SUP][SUP]7[/SUP], Das SR[SUP]11,[/SUP][SUP]12[/SUP].
[h=3]Author information[/h]
[h=3]Abstract[/h] Development of antiviral drug resistance is a continuous concern for viruses with high mutation rates such as influenza. The use of antiviral drugs targeting host proteins required for viral replication is less likely to result in the selection of resistant viruses than treating with direct-acting antivirals. The iminosugar UV-4B is a host-targeted glucomimetic that inhibits endoplasmic reticulum α-glucosidase I and II enzymes resulting in improper glycosylation and misfolding of viral glycoproteins. UV-4B has broad-spectrum antiviral activity against diverse viruses including dengue and influenza. To examine the ability of influenza virus to develop resistance against UV-4B, mouse-adapted influenza virus was passaged in mice in the presence or absence of UV-4B and virus isolated from lungs was used to infect the next cohort of mice, for five successive passages. Deep sequencing was performed to identify changes in the viral genome during passaging in the presence or absence of UV-4B. Relatively few minor variants were identified within each virus and the ratio of nonsynonymous to synonymous (dN/dS) substitutions of minor variants confirmed no apparent positive selection following sustained exposure to UV-4B. Three substitutions (one synonymous in PB2, one nonsynonymous in M and PA each) were specifically enriched (>3%) in UV-4B-treated groups at passage five. Recombinant viruses containing each individual or combinations of these nonsynonymous mutations remained sensitive to UV-4B treatment in mice. Overall, these data provide evidence that there is a high genetic barrier to the generation and selection of escape mutants following exposure to host-targeted iminosugar antivirals.
PMID: 31097731 DOI: 10.1038/s41598-019-43030-y
Free full text