Chapter 2 : Enterovirus Genetics

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The genetic analysis of enteroviruses was revolutionized by the advent of genetic engineering techniques and more specifically by two discoveries. First, the genetic map of the poliovirus genome was determined through sequence analysis of viral RNA and virus-encoded proteins. Second, cDNA copies of picornavirus genomes were found to yield infectious virus when they were introduced into mammalian cells either as DNA or, more efficiently, as RNA transcripts. This development has permitted facile generation and analysis of mutant viruses at the molecular level. Genetic studies based on these two developments have contributed substantially to our understanding of the biology and pathogenic properties of enteroviruses. Genetic dissection of the enteroviral 5' nontranslated region (NTR) and polyprotein has been facilitated by the recent development of a strategy that involves insertion of an internal ribosomal entry site (IRES) element into the enteroviral genome. The evolutionary role of recombination in the generation of enterovirus genomes is discussed in detail in this chapter. Generation of enterovirus mutants is the first critical step in their genetic analysis. Mutants with single defined genetic alterations are preferred starting materials for genetic experiments, and they can now be generated readily by manipulation of infectious cDNA clones, and genotypes can be confirmed by recloning and sequencing. Enteroviral mutants have been generated by a variety of strategies. The chapter talks about genetic complementation, reversion, recombination, and genetics of pathogens.

Citation: Hellen C, Wimmer E. 1995. Enterovirus Genetics, p 25-48. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch2
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Image of FIGURE 1

Genetic organization of poliovirus type 1 (Mahoney), the type member of genus Enterovirus of Picornaviridae. The polyprotein encoded by the single ORF is shown as an elongated rectangle, the 5' and 3' noncoding regions are shown as lines, and the genome-linked protein (VPg) is indicated by a black circle. Cleavage sites between individual viral proteins are shown above the genome at appropriate locations; these proteins are described within the rectangle according to the L434 nomenclature ( ); the capsid proteins 1AB, 1A, IB, 1C, and ID are commonly referred to as VPO, VP4, VP2, VP3, and VP1, respectively. The proteinases 2Apro, 3Cpro, and 3CDpro are represented by shaded boxes. The structural protein precursor PI and the nonstructural protein precursors P2 and P3 are indicated above the polyprotein.

Citation: Hellen C, Wimmer E. 1995. Enterovirus Genetics, p 25-48. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch2
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Image of FIGURE 2

Schematic depiction of the secondary structure of the 5′ nontranslated region of poliovirus based on previous models ( ). The nomenclature of structural elements is described elsewhere ( ). Boundaries of IRES are indicated by a dotted line; the Yn and AUG elements of the Yn-Xm-AUG motif are represented by shaded and black rectangles, respectively; and the initiating codon of the viral polyprotein is represented by an open rectangle.

Citation: Hellen C, Wimmer E. 1995. Enterovirus Genetics, p 25-48. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch2
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Image of FIGURE 3

Relationship among members of the Enterovirus genus, according to aligned sequences of their genomic RNAs. Relationships are presented graphically as a minimum length, binary parsimonious rooted cladogram, calculated by using heuristic methods. Abbreviations: BEV, bovine enterovirus; CoxA, coxsackie A virus; CoxB, coxsackie B virus; Echo, echovirus; EV, enterovirus; Polio, poliovirus; SVD, swine vesicular disease virus.

Citation: Hellen C, Wimmer E. 1995. Enterovirus Genetics, p 25-48. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch2
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Image of FIGURE 4

Genetic organization of dicistronic poliovirus mRNA genomes.The 5'–terminal 108–nt fragment of the PV1(M) 5' NTR is shown as a cloverleaf, the downstream segments of the 5' NTR (including the IRES) are shown as thin zigzag lines, and the segments of the EMCV 5' NTR inserted into the poliovirus genome are shown as thick zigzag lines. EMCV segments correspond to nt 260 to 848 (in plasmids 1 and 4), 260 to 833 (in plasmids 5 to 11), and 435 to 833 (in plasmid 3). Stippled rectangles represent poliovirus coding regions, and the cross-hatched rectangles represent the chloramphenicol acetyltransferase (CAT) and luciferase (LUC) coding regions. Viruses recovered after transfection of mRNA transcripts into HeLa cells are described with standard nomenclature; (–) indicates that a viable virus was not recovered.

Citation: Hellen C, Wimmer E. 1995. Enterovirus Genetics, p 25-48. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch2
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Image of FIGURE 5

Complementation map of poliovirus. Deletions identified in DI particles ( ) are shown as rectangles; other mutations are shown as circles. Open circles represent recessive mutations that can be complemented by wt or other mutant viruses ( ), black circles represent as-dominant mutations that cannot be complemented or rescued ( ), and gray circles represent trans-dominant mutations that can inhibit the growth of coinfecting virus ( ). Adapted from a figure by Kirkegaard ( ).

Citation: Hellen C, Wimmer E. 1995. Enterovirus Genetics, p 25-48. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch2
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Image of FIGURE 6

Steps in the replication of poliovirus RNA. Parental positive-sense virion RNA is transcribed in a primer-dependent manner. A replicative intermediate (RI) form (A) consisting of a single positive-sense template (solid line) and multiple nascent negative-strands (dashed lines) has not been detected, so that more probable intermediates in negative-strand synthesis could be mainly single stranded (B) or double stranded (C). Elongation of nascent negative-sense strand (C) yields RF double-stranded RNA (D).This product of replication may be an intermediate in the synthesis of positive-sense replicative intermediate structure F or G. The first step in this process may be the partial melting of RF RNA, leading to the formation of terminal cloverleaf structures; the cloverleaf formed on the positive-sense strand may be stabilized by a complex consisting of 3CDpro and host factors or other viral polypeptides (E). The final product is single-stranded positive-sense genomic virion RNA (H). The generation of free negative-sense strands is unlikely. The 5'-terminal VPg moieties are represented by solid circles.

Citation: Hellen C, Wimmer E. 1995. Enterovirus Genetics, p 25-48. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch2
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Image of FIGURE 7

Two models for recombination between poliovirus genomes based on proposals by Romanova et al. ( ) and (model 1) Jarvis and Kirkegaard ( ) (model 2). In model 1, self-complementary regions are denoted as a and a'. Solid lines correspond to genomic template RNA molecules, and dashed lines correspond to the complementary RNA strand. Homologous recombination sites are represented by black rectangles. Heteroduplex formation results in base pairing of two genome molecules that are brought close together (step A).The viral RNA polymerase copies one RNA molecule from the 3' end and may pause within the region of intermolecular base pairing (step B), dissociate, and reassociate with a homologous site in the second RNA molecule (step C). Synthesis of a recombinant minus-strand molecule then continues (step D). In model 2, solid lines represent genomic template RNA molecules, broken lines correspond to nascent minus strands, and dashed lines correspond to invading positive-sense template RNA molecule. The viral RNA polymerase copies one RNA molecule from the 3' end and may pause, slide backward, and unpair a few bases of the nascent strand (step A), which then associates with an invading acceptor RNA strand (step B). Synthesis of a recombinant minus-strand molecule then continues (step C).

Citation: Hellen C, Wimmer E. 1995. Enterovirus Genetics, p 25-48. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch2
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Image of FIGURE 8

Locations of attenuating mutations in poliovirus types 1 and 3 (Sabin) strains. (A) Locations of nucleotide and amino acid differences between the P1/Mahoney/41 (parent) and P1/LS-c, 2ab (vaccine) strains are indicated by lines above and below the genomic RNA, respectively. There are 55 nucleotide differences between the genomes of these two PV type 1 strains ( ). (B) Nucleotide and predicted amino acid sequence differences between P3/Leon/37 (parent) and P3/Leon 12afb (Sabin vaccine) poliovirus type 3 strains ( ). Genomic RNA and its genetic organization are shown at the top, and the length of the poliovirus genome from the ′' terminus is indicated at the bottom. An additional recently reported difference between these two strains ( ) at nt 2493, producing an amino acid change at residue 6 of the capsid protein VP1, is not shown.

Citation: Hellen C, Wimmer E. 1995. Enterovirus Genetics, p 25-48. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch2
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Image of FIGURE 9

Domain V of the 5' noncoding regions of poliovirus types 1 (Mahoney), 2 (Lansing), and 3 (Leon), based on the structure proposed by Pilipenko et al. ( ).The nucleotide substitutions that attenuate the Sabin vaccine strains of these three serotypes are circled, and their locations are indicated.

Citation: Hellen C, Wimmer E. 1995. Enterovirus Genetics, p 25-48. In Rotbart H (ed), Human Enterovirus Infections. ASM Press, Washington, DC. doi: 10.1128/9781555818326.ch2
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