Genome of Horsepox Virus

Abstract

The genus Orthopoxvirus includes members of the family Poxviridae historically relevant to human health-variola virus (VARV), the etiologic agent of smallpox, and vaccinia virus (VACV), the vaccine virus used to eradicate smallpox (32). Other orthopoxviruses (OPVs), similar to VACV, are zoonotic and significant for human health, including monkeypox virus (MPXV) and cowpox virus (CPXV) (33). Still others, similar to VARV, remain restricted to specific, albeit nonhuman, hosts, including camelpox virus (CMLV) in camels and ectromelia virus (ECTV) in mice. Recent developments have heightened interest in OPV virulence and host range, including the threats of deliberate VARV reintroduction, virulence associated with preemptive smallpox vaccination and use of VACV-based recombinant vaccines, and the introduction of MPXV into the United States (16,28,69,83). Isolation of OPV from infected animals and humans during limited disease outbreaks or from animals in the wild suggests that additional OPVs circulating in nature could represent an emerging disease threat (24,25,27,32,46,49,50,90).Given their importance, OPVs have been extensively studied as models of poxviral molecular biology, genomics, genetics, and virus-host interaction (19,33,59). Research has revealed that OPVs contain approximately 170 to 230 genes, with those in central genomic regions generally involved in poxviral intracytoplasmic replication and those in terminal genomic regions involved or potentially involved in virus-host interactions, including manipulation of host immune or cellular apoptotic responses (4,19,59,60,82,87).Comparative analysis of completely sequenced OPV genomes, including most known OPV species and several strains of VARV, VACV and the closely related rabbitpox virus (RPXV), MPXV, CMLV, and CPXV has begun to reveal the degree of variability within the genus Orthopoxvirus, verifying that terminal genomic regions are the most variable and thus likely to contribute to the virulence and host range characteristics of different OPVs (2,9,21,22,36,39,51,52,54,58,78,80,81). The precise roles and contributions of many variable genes and gene complements in OPV virulence and host range, however, remain to be fully characterized. It is likely that complete genomic data from uncharacterized OPV isolates will aid in OPV gene identification and functional characterization, while also providing information regarding the pathogenic potential of the virus.

Evolution of and Evolutionary Relationships between Extant Vaccinia Virus Strains

“…Curiously, the virus that was eventually used to eradicate smallpox was one now called vaccinia virus (VACV), another orthopoxvirus but one that is clearly different from any known strain of CPXV. The biological origin of VACV is uncertain, although it has been suggested that a horsepox-like virus was an ancestor, even though a surviving horsepox virus (HPXV) ge-nome harbors many extra genes (8). This hypothesis is supported by Jenner's report that he obtained his later inocula from an infection in horses called "grease" (5).…”

“…DNA containing DVX_010 to DVX_013 replaces sequences in this gap and is present in both VACV TIRs, while HPXV/CPXV retains these sequences only at the right end of the genome. It has been suggested that the VACV telomeres were created by a transposition of these sequences from the right to the left end of an HPXV-like genome (8). However, since the HPXV TIR still harbors homologs of the genes DVX_001 to DVX_009, it is more likely that the entire region (from DVX_013 to DVX_001 and corresponding to HPXV_196 to the end of the HPXV genome) transposed from the right to the left end of this hypothetical common ancestor.…”

“…This analysis supports the hypothesis that a stock of virus sharing features characteristic of both HPXV and VACV lies at the root of these trees. Moreover, the relatively short length of the Dryvax branches, the nearness to the tree's roots, and the detection of HPXV-like sequences in one particular clone (8) suggested that Dryvax may still retain some of the features of this hypothetical common ancestor. To gain further insights into these relationships, we turned to a third method, which uses the TIRs and the TIR boundaries to provide additional insights into VACV evolution.…”

Cowpox Virus Evades CTL Recognition and Inhibits the Intracellular Transport of MHC Class I Molecules

“…An alternative explanation is that VV originates from a virus that lacks the ability to retain MHC class I. Although the origin of VV is not entirely clear, recent evidence suggests that VV is much more closely related to horsepox virus (HSPV) than to either CPV or MPV (39). Moreover, experimental infection of horses with VV can produce the same clinical symptoms as those of HSPV (40).…”

When good vaccines go wild: Feral Orthopoxvirus in developing countries and beyond

“…During the years of vaccination, the use of the live vaccine virus we now call vaccinia virus replaced the original cowpox virus, but the exact period in history that the change occurred is unknown. Today we know that vaccinia virus is genetically and biologically distinct from the poxviruses that we now call cowpox and horsepox viruses [21].…”