Research Summary

Our group has been interested in two important problems in virology. The first is the nature of the mechanisms of genomic packaging in viruses that have complex RNA genomes. In several cases, viruses can package a multipartite RNA genome such that each virion has one each of the different genomic segments. We have been studying the packaging of the genomes of the Cystoviridae, bacteriophages with a genome composed of three segments of double-stranded RNA. We have developed a model for the packaging mechanism and have substantiated it experimentally. It is the only case where the mechanism of packaging has been elucidated for a multipartite genome. We are currently trying to identify the detailed molecular interactions involved in the specificity of the packaging.

The second problem is that of the fidelity of genomic replication in RNA viruses. Many of the most harmful viruses that affect humans have genomes composed of RNA. These viruses are able to reproduce their genetic material by means of an enzyme called RNA polymerase. A significant difference between the replication of RNA and DNA is that RNA copies contain many more errors than in DNA copies. This is primarily due to the fact that DNA copies are usually edited to remove mistakes, while there is no comparable RNA editing function. This increased level of error production is actually useful to viruses in that some of the errors lead to mutations that allow the virus to escape the immune surveillance of the host organisms. The mutations result in the virus being very adaptable to changes in its environment. However, if a virus makes too many mistakes in copying its genome it will become debilitated or "lose fitness."

It has been proposed that viral RNA polymerases are constructed so that they offer maximum adaptability consistent with acceptable loss of fitness, and that any increase in error production would be fatal to the virus. This proposal has never been tested. Our group has developed a reverse genetics system that allows us to construct a virus that is easily screened for increased mutation production. We are isolating mutants of the virus that have changed their RNA polymerase so that they produce more errors than normal. This will allow us to determine whether the consensus is true and will increase our understanding of the price of adaptability for disease-causing viruses.




Recent Articles

Mindich, L. (2006).
Phages with segmented double-stranded RNA genomes.
In: The Bacteriophages (R. Calendar, ed.), Oxford University Press, New York. 197-207

Jian Qiao, Xueying Qiao, Yang Sun and Leonard Mindich (2005).
In vivo studies of genomic packaging in the dsRNA bacteriophage phi8.
BMC Microbiol. 5(1):10.

Mindich L. (2004).
Packaging, replication and recombination of the segmented genome of bacteriophage Phi6 and its relatives.
Virus Res. 2004 Apr;101(1):83-92 D.H. Bamford and L.Mindich, Guest Editors
PMID: 15010219
Abstract  |  Full Article

Sun Y, Qiao X, Mindich L. (2004).
Construction of carrier state viruses with partial genomes of the segmented dsRNA bacteriophages.
Virology. 2004 Feb 20;319(2):274-9
PMID: 14980487
Abstract  |  Full Article

Qiao X, Qiao J, Mindich L. (2003).
Analysis of specific binding involved in genomic packaging of the double-stranded-RNA bacteriophage phi6.
J Bacteriol. 2003 Nov;185(21):6409-14
PMID: 14563876
Abstract  |  Full Article

Qiao J, Qiao X, Sun Y, Mindich L. (2003).
Isolation and analysis of mutants of double-stranded-RNA bacteriophage phi6 with altered packaging specificity.
J Bacteriol. 2003 Aug;185(15):4572-7
PMID: 12867467
Abstract  |  Full Article

Sun Y, Qiao X, Qiao J, Onodera S, Mindich L. (2003).
Unique properties of the inner core of bacteriophage phi8, a virus with a segmented dsRNA genome.
Virology. 2003 Apr 10;308(2):354-61
PMID: 12706084
Abstract  |  Full Article

Onodera S, Sun Y, Mindich L (2001).
Reverse genetics and recombination in Phi8, a dsRNA bacteriophage.
Virology 2001 Jul 20;286(1):113-8
PMID: 11448164
Abstract  |  Full Article



Hoogstraten, D., Qiao, X., Sun, Y., Hu, A., Onodera, S. and Mindich, L. (2000)
Initial characterization of phi8, a bacteriophage containing three dsRNA genomic segments and distantly related to phi6.
Virology 272: 218-224

Qiao, X, Qiao, J., Onodera, S. and Mindich, L. (2000)
Characterization of phi13, a bacteriophage containing three dsRNA genomic segments and distantly related to phi6.
Virology 275: 218-224

Mindich, L. (1999)
Reverse Genetics of the dsRNA Bacteriophage phi6 Advances in Virus Research.
53: 341-353

Mindich, L. (1999)
The precise packaging of the three genomic segments of dsRNA bacteriophage phi6.
Microbiol. and Mol. Biol. Revs.63: 149-160

Mindich, L., Qiao, X and Qiao, J., Onodera, S., Romantschuk, M. and Hoogstraten, D. (1999)
Isolation of additional bacteriophages with genomes of segmented double-stranded RNA.
J. Bact. 181:4505-4508

de Haas, F., Paatero, A. O., Mindich, L., Bamford, D. H. and Fuller, S. D. (1999)
A symmetry mismatch at the site of RNA packaging in the polymerase complex of dsRNA bacteriophage phi6.
J. Mol. Biol. 294: 357-372

Onodera, S., Qiao, X., Qiao, J. and Mindich, L. (1998)
Directed changes in the number of genomic segments of dsRNA bacteriophage F6.
Proc. Nat. Acad. Sci. USA 95:3920-3924

Paatero, A. O., Mindich, L. and Bamford, D. H. (1998)
Mutational analysis of the role of the NTPase P4 in the assembly of the RNA polymerase complex of bacteriophage phi6.
J. Virol. 72: 10058-10065

Onodera, S., Qiao, X., Qiao, J. and Mindich, L. (1998)
Isolation of a mutant that changes genomic packaging specificity in phi6.
Virology 252: 438-442

Qiao, X., Qiao, J. and Mindich, L. (1997)
An in vitro system for the investigation of heterologous RNA recombination.
Virology 227: 103-110

Qiao, X., Qiao, J. and Mindich, L. (1997)
Stoichiometric packaging of the three genomic segments of dsRNA bacteriophage F6.
Proc. Nat. Acad. Sci. USA 94: 4074-4079

Mindich, L. (1995)
Heterologous recombination in the segmented dsRNA genome of bacteriophage F6.
Seminars in Virology 6: 75-83

Qioa, X., Qiao, J. and Mindich, L. (1995)
Interference of bacteriophage F6 genomic RNA packaging by hairpin structures.
J. Virol. 69: 5502-5505

Qiao, X., Casini, G., Qiao, J. and Mindich, L. (1995).
In vitro packaging of individual genomic segments of bacteriophage F6 RNA: serial dependence relationships.
J. Virol. 69: 2926-2931

Onodera, S., Qiao, X., Qiao, J. and Mindich, L. (1995)
Acquisition of a fourth genomic segment in bacteriophage F6: a bacteriophage with a genome of three segments of dsRNA.
Virology 212: 204-212

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