Succession of Mutations in the Sabin Strain of Type 3 Poliovirus Replicating in the Central Nervous System of Monkeys

Lu, Zhengbin; Asher, David M.; Levenbook, Inessa S.; Chumakov, Konstantin

doi:10.1006/viro.1996.0316

Cited by 9 publications

(3 citation statements)

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“…In a complex environment, the ability to generate a quasispecies may allow virus populations to respond and adapt fast (43)(44)(45)(46). Fidelity variants with wild-type-like replication kinetics are valuable tools to understand the roles of genetic diversity and mutation frequency in viral fitness and to evaluate the antiviral treatments (47).…”

Section: Discussionmentioning

confidence: 99%

Attenuation of Human Enterovirus 71 High-Replication-Fidelity Variants in AG129 Mice

Meng

Kwang

2014

J Virol

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In a screen for ribavirin resistance, a novel high-fidelity variant of human enterovirus 71 (EV71) with the single amino acid change L123F in its RNA-dependent RNA polymerase (RdRp or 3D) was identified. Based on the crystal structure of EV71 RdRp, L123 locates at the entrance of the RNA template binding channel, which might form a fidelity checkpoint. EV71 RdRp-L123F variants generated less progeny in a guanidine resistance assay and virus populations with lower mutation frequencies in cell culture passage due to their higher replication fidelity. However, compared with wild-type viruses, they did not show growth defects. In vivo infections further revealed that high-fidelity mutations L123F and G64R (previously reported) negatively impacted EV71 fitness and greatly reduced viral pathogenicity alone or together in AG129 mice. Interestingly, a variant with double mutations, RG/B4-G64R/L123F (where RG/B4 is an EV71 genotype B4 virus constructed by reverse genetics [RG])showed higher fidelity in vitro and less virulence in vivo than any one of the above two single mutants. The 50% lethal dose (LD 50 ) of the double mutant increased more than 500 times compared with the LD 50 of wild-type RG/B4 in mice. The results indicated that these high-fidelity variants exhibited an attenuated pathogenic phenotype in vivo and offer promise as a live attenuated EV71 vaccine. IMPORTANCEThe error-prone nature of the RNA-dependent RNA polymerase (RdRp) of RNA viruses during replication results in quasispecies and aids survival of virus populations under a wide range of selective pressures. Virus variants with higher replication fidelity exhibit lower genetic diversity and attenuated pathogenicity in vivo. Here, we identified a novel high-fidelity mutation L123F in the RdRp of human enterovirus 71 (EV71). We further elucidated that EV71 variants with the RdRp-L123F mutation and/or the previously identified high-fidelity mutation RdRp-G64R were attenuated in an AG129 mouse model. As EV71 has emerged as a serious worldwide health threat, especially in developing countries in the Asia-Pacific region, we urgently need EV71 vaccines. Learning from the poliovirus vaccination, we prefer live attenuated EV71 vaccines to inactivated EV71 vaccines in order to effectively control EV71 outbreaks at low cost. Our results imply a new means of attenuating EV71 and reducing its mutation rate at the same time.

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Section: Discussionmentioning

confidence: 99%

Attenuation of Human Enterovirus 71 High-Replication-Fidelity Variants in AG129 Mice

Meng

Kwang

2014

J Virol

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“…In a complex environment such as within a mouse, the ability to generate a quasispecies may allow virus populations to respond to the different environments they encounter during spread between tissues and in reaction to changing pressure of the host immune response. In monkeys infected with a vaccine strain of poliovirus, distinct mutations were observed to occur within 2 d post-infection, only to revert to the inoculated sequence later in the course of disease [21]. Furthermore, HIV is known to change its cell tropism from macrophage-tropic to T cell-tropic, during spread in many infected individuals [22–23].…”

Section: Discussionmentioning

confidence: 99%

Increased Fidelity Reduces Poliovirus Fitness and Virulence under Selective Pressure in Mice

2005

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RNA viruses have high error rates, and the resulting quasispecies may aid survival of the virus population in the presence of selective pressure. Therefore, it has been theorized that RNA viruses require high error rates for survival, and that a virus with high fidelity would be less able to cope in complex environments. We previously isolated and characterized poliovirus with a mutation in the viral polymerase, 3D-G64S, which confers resistance to mutagenic nucleotide analogs via increased fidelity. The 3D-G64S virus was less pathogenic than wild-type virus in poliovirus-receptor transgenic mice, even though only slight growth defects were observed in tissue culture. To determine whether the high-fidelity phenotype of the 3D-G64S virus could decrease its fitness under a defined selective pressure, we compared growth of the 3D-G64S virus and 3D wild-type virus in the context of a revertible attenuating point mutation, 2C-F28S. Even with a 10-fold input advantage, the 3D-G64S virus was unable to compete with 3D wild-type virus in the context of the revertible attenuating mutation; however, in the context of a non-revertible version of the 2C-F28S attenuating mutation, 3D-G64S virus matched the replication of 3D wild-type virus. Therefore, the 3D-G64S high-fidelity phenotype reduced viral fitness under a defined selective pressure, making it likely that the reduced spread in murine tissue could be caused by the increased fidelity of the viral polymerase.

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“…No common amino acids were found between the CSF and stool samples; however, position 54 was T in CSF and V in stools. Furthermore, none of the substitutions has been previously reported as associated with neurovirulence [ 7 , 8 ].…”

Section: Case In Discussionmentioning

confidence: 99%

Stem Cell Transplant in Immune-deficiency–associated Vaccine-derived Poliovirus

Ranchod,

Howard,

Roux

et al. 2024

Open Forum Infectious Diseases

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Patients with severe primary immunodeficiency are at risk for complications from live attenuated vaccines. Here, we report a case of a vaccine associated paralytic polio (VAPP) and Bacille Calmette-Guérin (BCG) disease in a 6-month-old girl with severe-combined immunodeficiency (SCID) due to homozygous recombinant activating gene 1 (RAG-1) deficiency. The patient was successfully treated with intravenous immunoglobulins and oral pocapavir for poliovirus, and anti-mycobacterial therapy for regional BCG disease, allowing stem cell transplant. Following transplantation, poliovirus type 3 with 13 mutations was detected from cerebrospinal fluid but not from stool, indicating ongoing viral evolution in the central nervous system despite pocapavir treatment. Clinical improvement and immune reconstitution allowed the patient to be successfully discharged with no further detection of poliovirus.

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Succession of Mutations in the Sabin Strain of Type 3 Poliovirus Replicating in the Central Nervous System of Monkeys

Cited by 9 publications

References 0 publications

Attenuation of Human Enterovirus 71 High-Replication-Fidelity Variants in AG129 Mice

Attenuation of Human Enterovirus 71 High-Replication-Fidelity Variants in AG129 Mice

Increased Fidelity Reduces Poliovirus Fitness and Virulence under Selective Pressure in Mice

Stem Cell Transplant in Immune-deficiency–associated Vaccine-derived Poliovirus

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