Live Variola Virus Considerations for Continuing Research (2009) / Chapter Skim
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3 Comparative Poxvirology
3 Comparative Poxvirology
Pages 27-48
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From page 27... ...
Taking advantage of insights from comparative virology is particularly important because experiments with live variola virus must focus on critical questions. Knowledge of the related poxviruses can inform the design and refinement of experiments for which live variola virus is necessary.
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From page 28... ...
. The Orthopoxvirus genus includes many of the known poxviruses that naturally infect mammals, including vaccinia, the prototypical poxvirus, as well as two of the three poxviruses that have most commonly infected humans, variola and monkeypox virus; the third, molluscum contagiosum virus, is a member of Molluscipoxvirus.
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From page 29... ...
Poxvirus genes are usually nonoverlapping but closely spaced, and are arranged in blocks such that genes in the outer quadrants of the genome are transcribed toward the end of the genome in closest proximity, while genes in the central quadrants are transcribed toward the center of the genome. An analysis of 21 Poxviridae complete genome sequences in 2003 revealed a common set of 49 genes and an additional 41 genes shared by the chordopoxviruses (Upton et al., 2003)
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30 LIVE VARIOLA VIRUS FIGURE 3-1 Electron microscopy of orthopoxvirus structure.
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From page 31... ...
Gene loss, fragmentation, and duplication all appear to have played important roles in poxvirus evolution, with subsequent restriction of virus host range. Complete genome sequences and comparative analysis have suggested the basis for differences in virulence among strains of the same orthopoxvirus species, as illustrated by monkeypox virus (MPXV)
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From page 32... ...
More genomic information about variola virus isolates, coupled with clinical data on disease severity in the cases from which the virus was recovered, has the potential to elucidate factors influencing the virulence of variola. VirAL life cycle Variola virus, like all orthopoxviruses, replicates solely in the cytoplasm of infected cells (see Figure 3-3)
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From page 33... ...
core envelope Cytoplasm DNA Attachment Entry Uncoating DNA replication enzymes Transcription Factors WV Nucleus DNA packaging Concatamer resolution EV Wrapping Maturation MV IV Crescents Golgi bodies Virus Factory 33 FIGURE 3-3 Orthopoxvirus replication. Figure 3-3 REV.eps broadside
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From page 34... ...
Intermediate gene expression utilizes viral transcription factors that are expressed as early proteins, as well as some host proteins. Late gene expression also uses distinct viral transcription factors, as well as some host factors.
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From page 35... ...
. A virally encoded protein kinase is also essential for replication; its primary role appears to be to phosphorylate and thus overcome the inhibitory action of a cytoplasmic DNA sensor.
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From page 36... ...
The ability of poxviruses to replicate and complete their viral life cycle in cells is dependent on many host-related factors, including cell type and species origin, cell cycle status, and intracellular signaling events leading to antiviral innate immunity and apoptosis. Identification of host range genes and elucidation of their interactions with
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From page 37... ...
The importance of the capacity to block the host cell response is demonstrated by the arrest of replication of vaccinia mutant strains lacking K1L at the stage of inter mediate gene transcription in Chinese hamster ovary cells. The conservation of this function, and hence its likely importance to other orthopoxviruses, was shown by the rescue of this mutant by expression of another ankyrinrepeat containing host range protein from cowpox, CP77 (Ramsey-Ewing and Moss, 1996)
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From page 38... ...
Over the last decade, significant advances have been made in the understanding of poxvirus–host interactions and viral immune modulatory genes. Antiviral innate immunity is critical for the host to contain a viral infection initially and to activate the adaptive immune responses that result in viral clearance.
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From page 39... ...
is a pleiotropic cytokine that mediates inflammation and apoptosis within the host. Many poxviruses, including variola virus, encode TNF receptor homologs (TNFRs)
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. Variola virus and monkeypox virus also have high-affinity c hemokine-binding proteins (Alejo et al., 2006; Jones et al., 2008)
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From page 41... ...
; variola virus encodes E3L and K3L homologs. Myxoma M11L, a virulence gene, encodes a mitochondria-targeted molecule that prevents apoptosis (Everett et al., 2000)
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From page 42... ...
After the vaccinia lesion at the site of inoculation has resolved, antiviral T cell and antibody responses decline rapidly before reaching a more long-lived plateau phase in which immunological memory is maintained for decades. During this memory phase, vaccinia-specific CD4+ and CD8+ T cell responses decline slowly, with an estimated half-life of 8–15 years (Crotty et al., 2003; Hammarlund et al., 2003)
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From page 43... ...
2006. Vaccinia virus infection a ttenuates innate immune responses and antigen presentation by epidermal dendritic cells.
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2008. Vaccinia virus subverts a mitochondrial antiviral signaling protein dependent innate immune response in keratinocytes through its dsRNA binding protein E3.
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2005. Role of viral factor E3L in modified vaccinia virus ankara infection of human HeLa cells: Regulation of the virus life cycle and identification of differentially expressed host genes.
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1996. Disruption of M-T5, a novel myxoma virus gene member of the poxvirus host range superfamily, results in dramatic attenuation of myxomatosis in infected European rabbits.
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1991. Myxoma virus expresses a secreted protein with homology to the tumor necrosis factor receptor gene family that contributes a viral virulence.
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From page 48... ...
2008. Loss of protein kinase PKR expression in human Hela cells complements the vaccinia virus E3L deletion mutant phenotype by restoration of viral protein synthesis.
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