Despite the success of the WHO-led smallpox eradication programme a quarter of a century ago, there remains considerable fear that variola virus, or other related pathogenic poxviruses such as monkeypox, could re-emerge and spread disease in the human population. Even today, we are still mostly ignorant about why most poxvirus infections of vertebrate hosts show strict species specificity, or how zoonotic poxvirus infections occur when poxviruses occasionally leap into novel host species. Poxvirus tropism at the cellular level seems to be regulated by intracellular events downstream of virus binding and entry, rather than at the level of specific host receptors as is the case for many other viruses. This review summarizes our current understanding of poxvirus tropism and host range, and discusses the prospects of exploiting host-restricted poxvirus vectors for vaccines, gene therapy or tissue-targeted oncolytic viral therapies for the treatment of human cancers.
Poxvirus host range varies markedly ? some viruses, such as variola and molluscum contagiosum virus (both of which are human-specific), exhibit strict species tropism, whereas others such as cowpox virus are able to infect multiple host species.
Members of four of the eight genera of chordopoxviruses can zoonotically infect man. For example, monkeypox virus can cause severe smallpox-like disease in humans that clinically resembles variola virus.
The species tropism that is exhibited by many poxviruses in terms of causing disease is frequently quite different from the range of cultured cells that can be infected by these viruses.
Specific host-cell receptors do not mediate the distinction between cells that are permissive as opposed to non-permissive for poxvirus infection. Rather, restrictive host cells fail to support the full replication cycle of the infecting poxvirus at a point downstream of binding and entry.
A variety of poxviral host-range genes have been identified that contribute to the control of permissive versus non-permissive infection of cultured mammalian cells. The gene products of these host-range genes regulate the ability of the virus to complete its cytoplasmic replication cycle.
The development of host-restricted vaccines, like modified vaccinia Ankara (MVA), that do not replicate in humans but that retain potent immunogenicity, will provide safer platforms for recombinant vaccines.
Another advance has been the development of poxvirus-based oncolytic vectors that replicate preferentially in human tumour cells.