The Complete Genomic Sequence of the Modified Vaccinia Ankara Strain: Comparison with Other Orthopoxviruses

Abstract

The complete genomic DNA sequence of the highly attenuated vaccinia strain modified vaccinia Ankara (MVA) was determined. The genome of MVA is 178 kb in length, significantly smaller than that of the vaccinia Copenhagen genome, which is 192 kb. The 193 open reading frames (ORFs) mapped in the MVA genome probably correspond to 177 genes, 25 of which are split and/or have suffered mutations resulting in truncated proteins. The left terminal genomic region of MVA contains four large deletions and one large insertion relative to the Copenhagen strain. In addition, many ORFs in this region are fragmented, leaving only eight genes structurally intact and therefore presumably functional. The inserted DNA codes for a cluster of genes that is also found in the vaccinia WR strain and in cowpox virus and includes a highly fragmented gene homologous to the cowpox virus host range gene, providing further evidence that a cowpox-like virus was the ancestor of vaccinia. Surprisingly, the central conserved region of the genome also contains some fragmented genes, including ORF F5L, encoding a major membrane protein, and ORFs F11L and O1L, encoding proteins of 39.7 and 77.6 kDa, respectively. The right terminal genomic region carries three large deletions all classical poxviral immune evasion genes and all ankyrin-like genes located in this region are fragmented except for those encoding the interleukin-1 beta receptor and the 68-kDa ankyrin-like protein B18R. Thus, the attenuated phenotype of MVA is the result of numerous mutations, particularly affecting the host interactive proteins, including the ankyrin-like genes, but also involving some structural proteins.

Vaccinia virus impairs directional migration and chemokine receptor switch of human dendritic cells

“…Infection with the WR strain even slightly enhanced cell motility of infected DC, which corresponds to recently published data showing that WR, but not MVA, is capable of inducing motility and undirected migration in infected cells [43]. In this context, it is also important to mention that the VV strains WR and MVA are not known to encode for so-called viral chemokine-binding-proteins (vCKBP) [26,44,45], which could otherwise explain these results with the viral clearance of chemokines by means of chemokine sequestration. We therefore proposed a mechanism of viral interference with signal transduction downstream of the surface level of chemokine receptors.…”

Modified vaccinia virus Ankara protein F1L is a novel BH3-domain-binding protein and acts together with the early viral protein E3L to block virus-associated apoptosis

“…13,14 We have previously generated the mutant virus MVA-DE3L deficient in E3L coding sequences (open reading frame 050, transcribed leftward through nucleotides 43 269 to 42 697 in the MVA genome). 15,16 Intriguingly, unlike MVA, MVA-DE3L caused apoptosis in infected CEF cells. 15 Furthermore, a vaccinia virus mutant lacking E3L has been reported to cause apoptosis in HeLa cells.…”

“…Interestingly, the open reading frame encoding F1L is highly conserved between the MVA genome (ORF 029, leftward transcription through nucleotides 26 046 to 25 378, 98% amino-acid identity and vaccinia virus strain Copenhagen). 16 Thus, many viruses can protect infected cells against experimental insults. It has, however, not been well explored what the physiological function of viral antiapoptotic proteins is on a molecular level.…”

Generation and evaluation of a recombinant modified vaccinia virus Ankara vaccine for rabies

“…During passage on these cells, the virus adaptation resulted in six major genomic openUP (June 2007) deletions of about 31,000 base pairs (or 15% of the wild type Vaccinia virus Ankara genome) [31] and [32]. Most of the deleted and truncated genes have been shown to be immuno-regulators, or involved in the host range of the virus and multiple gene defects will have to be corrected for reversion to wild type [32], [33], [34] and [35].…”

“…Most of the deleted and truncated genes have been shown to be immuno-regulators, or involved in the host range of the virus and multiple gene defects will have to be corrected for reversion to wild type [32], [33], [34] and [35]. MVA virus has been proven to be phenotypically and genotypically stable and although the virus fails to productively infect most mammalian cell lines tested (including cells of human origin), recombinant genes are still efficiently expressed in non-permissive cells [34], [35], [36] and [37].…”