Characterization of Poliovirus Variants Selected for Resistance to the Antiviral Compound V-073

Li, Hongmei; Roberts, Jason A.; Moore, Deborah; Anderson, Barbara; Pallansch, Mark A.; Pevear, Daniel C.; Collett, Marc S.; Oberste, M. Steven

doi:10.1128/aac.00539-12

Cited by 25 publications

(23 citation statements)

References 16 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, populations of this very sensitive virus always contain tiny proportions (depending on the drug concentration tested) of guanidine-resistant (g r ) mutants (61), or even mutants whose growth requires the presence of this drug (62; also see below). The presence of drug-resistant and drug-dependent variants in largely sensitive populations has also been reported for other picornaviruses and other inhibitors (63)(64)(65)(66)(67)(68)(69)(70)(71). Different variants within heterogeneous viral populations may complement each other in performing some functions, as appears to be the case with poliovirus (10,14,22,32), although the converse situation, negative trans-dominance of debilitating mutations, has also been documented (72,73).…”

Section: Introductionmentioning

confidence: 80%

Emergency Services of Viral RNAs: Repair and Remodeling

Agol

Gmyl

2018

Microbiol Mol Biol Rev

View full text Add to dashboard Cite

Reproduction of RNA viruses is typically error-prone due to the infidelity of their replicative machinery and the usual lack of proofreading mechanisms. The error rates may be close to those that kill the virus. Consequently, populations of RNA viruses are represented by heterogeneous sets of genomes with various levels of fitness. This is especially consequential when viruses encounter various bottlenecks and new infections are initiated by a single or few deviating genomes. Nevertheless, RNA viruses are able to maintain their identity by conservation of major functional elements. This conservatism stems from genetic robustness or mutational tolerance, which is largely due to the functional degeneracy of many protein and RNA elements as well as to negative selection. Another relevant mechanism is the capacity to restore fitness after genetic damages, also based on replicative infidelity. Conversely, error-prone replication is a major tool that ensures viral evolvability. The potential for changes in debilitated genomes is much higher in small populations, because in the absence of stronger competitors low-fit genomes have a choice of various trajectories to wander along fitness landscapes. Thus, low-fit populations are inherently unstable, and it may be said that to run ahead it is useful to stumble. In this report, focusing on picornaviruses and also considering data from other RNA viruses, we review the biological relevance and mechanisms of various alterations of viral RNA genomes as well as pathways and mechanisms of rehabilitation after loss of fitness. The relationships among mutational robustness, resilience, and evolvability of viral RNA genomes are discussed.

show abstract

Section: Introductionmentioning

confidence: 80%

Emergency Services of Viral RNAs: Repair and Remodeling

Agol

Gmyl

2018

Microbiol Mol Biol Rev

View full text Add to dashboard Cite

show abstract

“…As a candidate compound of capsid-binding inhibitors, the effectiveness of V-073 (previously designated SCH 48973) on in vitro PV infection and in a mouse infection model has been intensively analyzed in terms of the resistant mutation, pathogenicity of resistant mutants, and effects on immunization with IPV (28)(29)(30)(31)(32). To date, several enviroxime-like compounds have been identified, including TTP-8307 (33), some cellular protein kinase inhibitors (GW5074 and Flt3 inhibitor II) (34,35), and a bifunctional antienterovirus compound, AN-12-H5, which targets the replication process of PV and enterovirus 71 (EV71) and also an early stage of EV71 infection (36).…”

mentioning

confidence: 99%

Oxysterol-Binding Protein Family I Is the Target of Minor Enviroxime-Like Compounds

Arita

Kojima

Nagano

et al. 2013

J Virol

104

121

View full text Add to dashboard Cite

Enviroxime is an antipicornavirus compound that targets host phosphatidylinositol 4-kinase III beta (PI4KB) activity for its antipicornavirus activity. To date, several antipoliovirus (PV) compounds similar to enviroxime that are associated with a common resistance mutation in viral protein 3A (a G5318A [3A-Ala70Thr] mutation in PV) have been identified. Most of these compounds have a direct inhibitory effect on PI4KB activity, as well as enviroxime (designated major enviroxime-like compounds). However, one of the compounds, AN-12-H5, showed no inhibitory effect on PI4KB and was considered to belong to another group of enviroxime-like compounds (designated minor enviroxime-like compounds). In the present study, we performed a small interfering RNA (

show abstract

“…This shows that the amino acid substitutions found in the variants offer little advantage or disadvantage for the variants, and that the variants will replicate to the same extent as the parental strain in the absence of the VHH. This also has been observed for other neutralization escape variants against poliovirus types 1, 2, and 3 (39,40).…”

Section: Discussionmentioning

confidence: 63%