Poxvirus vectors: orphaned and underappreciated

When one considers the choice of viral vectors for use in gene therapy systems, candidates usually include adenovirus and retrovirus families and, in the case of retrovirus, most recently the HIV-derived lentiviral vectors.These vectors have been chosen based on criteria such as tropism, duration of expression, and capacity to integrate in the host genome.A number of characteristics of their life cycle make poxviruses poor candidates for long-term expression, and, as a result, they are neglected by investigators and rarely represented in reviews and at conferences.However, vaccinia and its relatives may be ideal in immunotherapy applications, including their use as replicating agents that can be directed against solid tumors.Poxvirus vectors, which enable us, as immunologists, to revisit 1 of our greatest triumphs (Figure 1), can be used both to deliver recombinant vaccines and to effect in situ gene transfer to provide cytokines that promote the recognition and rejection of tumors. Vaccinia virus vectorsVaccinia virus and other members of the poxviridae are unusual in that they remain in the cytoplasm and use virally encoded polymerases to carry out replication and transcription.Thus, recombination of viral DNA into the genome is not of concern with vaccinia, as it is with other vectors, particularly retroviruses.The infectious cycle is divided into 3 phases.Early-phase genes, typically encoding proteins with enzymatic function, are expressed before replication.The expression of a small number of intermediate genes depends on replication of the genome and, in turn, drives expression of structural proteins and other products of the late genes (reviewed in ref. 1).Generally speaking, "late" vaccinia promoters drive gene expression more strongly than "early" vaccinia promoters, making late or early/late promoters attractive for controlling expression of transgenes.Vaccinia virus was the first widely used vaccine and resulted in the eradication of smallpox (variola; Figure 1).As such, vaccinia has the longest and most extensive history of use in humans.Over time, it has been recognized as a relatively safe agent, with infrequent serious side effects, although it does induce a vigorous immune response and can be lethal for those who are immunocompromised or have eczema (1).Although smallpox is highly contagious, transmission being mainly via the respiratory tract, vaccinia is much less so and can be easily confined under standard Biosafety Poxvirus vectors: orphaned and underappreciated