Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population

Vignuzzi, Marco; Stone, Jeffrey K.; Arnold, Jamie J.; Cameron, Craig Ε.; Andino, Raul

doi:10.1038/nature04388

Cited by 1,001 publications

(1,143 citation statements)

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“…2A), consistent with the lower rate of RNA catalysis associated with a G64S mutation (28). The G64S mutation was stably maintained in virus populations, consistent with previous studies (25)(26)(27); however, the G64S mutation had no effect on the lengths of poly(A) tails in virion RNA (Table 1), as described in further detail below. The G64T and G64D mutations, which were associated with defects in capsid polyprotein processing (see Fig.…”

Section: Resultssupporting

confidence: 73%

“…It is important to note, however, that HeLa cells are extremely permissive host cells that do not reveal every important, biologically relevant phenotype. For instance, a G64S 3D pol mutation has little impact on the specific infectivity of poliovirus RNA or the replication of poliovirus in HeLa cells (Table 1); however, this mutation has a dramatic impact on the replication and pathogenesis of poliovirus in animal models (26,27,31). Thus, the biological significance of slightly longer or shorter poly(A) tails in poliovirus RNA is yet to be determined.…”

Section: Discussionmentioning

confidence: 99%

“…The fidelity of RNA replication is reported to influence the quasispecies diversity and the pathogenesis of poliovirus infections (27). A G64S mutation in 3D pol renders poliovirus resistant to ribavirin (25), increases the fidelity of RNA replication (26), and attenuates poliovirus replication in mice (26,27,31).…”

Section: Discussionmentioning

confidence: 99%

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Structural Features of a Picornavirus Polymerase Involved in the Polyadenylation of Viral RNA

Kempf

Kelly²,

Springer

et al. 2013

J Virol

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Picornaviruses have 3= polyadenylated RNA genomes, but the mechanisms by which these genomes are polyadenylated during viral replication remain obscure. Based on prior studies, we proposed a model wherein the poliovirus RNA-dependent RNA polymerase (3D pol ) uses a reiterative transcription mechanism while replicating the poly(A) and poly(U) portions of viral RNA templates. To further test this model, we examined whether mutations in 3D pol influenced the polyadenylation of virion RNA. We identified nine alanine substitution mutations in 3D pol that resulted in shorter or longer 3= poly(A) tails in virion RNA. These mutations could disrupt structural features of 3D pol required for the recruitment of a cellular poly(A) polymerase; however, the structural orientation of these residues suggests a direct role of 3D pol in the polyadenylation of RNA genomes. Reaction mixtures containing purified 3D pol and a template RNA with a defined poly(U) sequence provided data consistent with a template-dependent reiterative transcription mechanism for polyadenylation. The phylogenetically conserved structural features of 3D pol involved in the polyadenylation of virion RNA include a thumb domain alpha helix that is positioned in the minor groove of the double-stranded RNA product and lysine and arginine residues that interact with the phosphates of both the RNA template and product strands.P icornaviruses, like many other positive-strand RNA viruses, have RNA genomes with variable-length 3= poly(A) tails (1). The poly(A) tails of picornaviruses are important for viability (2), with the length of the poly(A) tails influencing the magnitudes of both viral mRNA translation and RNA replication (3, 4). RNA sequences and structures within the 3= nontranslated region are reported to influence both the length of poly(A) tails in picornaviral RNA (5) and the efficiency of virus replication (6, 7). Viral RNA-dependent RNA polymerases (3D pol s) are predicted to catalyze the polyadenylation of picornaviral RNA in a template-dependent manner during viral RNA replication (8); however, the mechanisms by which RNA genomes are polyadenylated during viral RNA replication remain obscure. In particular, there is little understanding of the mechanisms regulating the length of poly(A) tails synthesized during RNA replication. The RNA-dependent RNA polymerases of negative-strand RNA viruses reiteratively transcribe a small poly(U) sequence within intergenic regions of the viral RNA genome to produce long poly(A) tails on viral mRNAs (9). In a similar manner, the poliovirus RNA-dependent RNA polymerase can reiteratively transcribe poly(A) and poly(U) sequences during viral RNA replication, producing poly(A) and poly(U) sequences longer than those in the respective template RNAs (8).Viral RNA-dependent RNA polymerases are well studied at the structural level (10-12), yet there have been no reports describing the structural features of viral polymerases involved in the polyadenylation of viral RNA. The RNA-dependent RNA polymerase of picornaviruses a...

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Section: Resultssupporting

confidence: 73%

Section: Discussionmentioning

confidence: 99%

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Structural Features of a Picornavirus Polymerase Involved in the Polyadenylation of Viral RNA

Kempf

Kelly²,

Springer

et al. 2013

J Virol

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“…16,17 Because the behavior of any particular variant may be influenced by the entire viral population, it has been suggested that the quasispecies, and not individual viral genomes, are the target of selection and random drift. 18,19 Early evolution of the viral quasispecies was shown to predict the clinical outcome of acute hepatitis C. 20,21 Likewise, the long-term viral evolution was shown to correlate with the severity of liver disease. 22,23 The HCV quasispecies has been well characterized for different viral genomic regions.…”

mentioning

confidence: 99%

Genetic and catalytic efficiency structure of an HCV protease quasispecies

Franco¹,

Parera²,

Aparicio³

et al. 2007

Hepatology

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The HCV nonstructural protein (NS)3/4A serine protease is not only involved in viral polyprotein processing but also efficiently blocks the retinoic-acid-inducible gen I and Toll-like receptor 3 signaling pathways and contributes to virus persistence by enabling HCV to escape the interferon antiviral response. Therefore, the NS3/4A protease has emerged as an ideal target for the control of the disease and the development of new anti-HCV agents. Here, we analyzed, at a high resolution (approximately 100 individual clones), the HCV NS3 protease gene quasispecies from three infected individuals. Nucleotide heterogeneity of 49%, 84%, and 91% were identified, respectively, which created a dense net that linked different parts of the viral population. Minority variants having mutations involved in the acquisition of resistance to current NS3/4A protease inhibitors (PIs) were also found. A vast diversity of different catalytic efficiencies could be distinguished. Importantly, 67% of the analyzed enzymes displayed a detectable protease activity. Moreover, 35% of the minority individual variants showed similar or better catalytic efficiency than the master (most abundant) enzyme. Nevertheless, and in contrast to minority variants, master enzymes always displayed a high catalytic efficiency when different viral polyprotein cleavage sites were tested. Finally, genetic and catalytic efficiency differences were observed when the 3 quasispecies were compared, suggesting that different selective forces were acting in different infected individuals. Conclusion: The rugged HCV protease quasispecies landscape should be able to react to environmental changes that may threaten its survival. (HEPATOLOGY 2007;45:899-910.)

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“…Incidentally, when analysing RNA viruses, virologists often consider the number of mutations in a genome with respect to another taken as a reference, e.g. the master sequence (see Crotty et al 2001;Vignuzzi et al 2006).…”

Section: Notice That the Equation For Virus Evolution Is Different Frmentioning

confidence: 99%

Error catastrophe for viruses infecting cells: analysis of the phase transition in terms of error classes

Alonso

Fort

2010

Phil. Trans. R. Soc. A.

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RNA viruses offer a very exciting arena in which to study evolution in 'real time' owing to both their high replication rate-many generations per day are possible-and their high mutation rate, leading to a large phenotypic variety. They can be regarded as a swarm of genetically related mutants around a dominant or master genetic sequence. This system is called a 'viral quasi-species'. Thus, a common framework to describe RNA viral dynamics is by means of the quasi-species equation (QSE). The QSE is in fact a system of a very large number of nonlinear coupled equations. Here, we consider a simpler formulation in terms of 'error classes', which groups all the sequences differing from the master sequence by the same number of genomic differences into one population class. From this, based on the analogies with Bose condensation, we use thermodynamic inspired observables to analyse and characterize the 'phase transition' through the socalled 'RNA virus error catastrophe'.

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Quasispecies diversity determines pathogenesis through cooperative interactions in a viral population

Cited by 1,001 publications

References 21 publications

Structural Features of a Picornavirus Polymerase Involved in the Polyadenylation of Viral RNA

Structural Features of a Picornavirus Polymerase Involved in the Polyadenylation of Viral RNA

Genetic and catalytic efficiency structure of an HCV protease quasispecies

Error catastrophe for viruses infecting cells: analysis of the phase transition in terms of error classes

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