Poxviruses: past, present and future

Abstract

The analysis of poxvirus genomes is complex, in part, because of their size (130–360 kb) and the fact that gene content is variable; a common set of 49 genes has been found in all sequenced poxviruses and an additional 41 genes are also present in all sequenced orthopoxviruses. As a group, poxviruses have a very broad range of eukaryotic hosts (including mammals, birds, reptiles and insects) and many poxvirus genes are associated with blocking host anti-viral responses. One consequence of this is that many poxvirus genes are not essential for growth in tissue culture and that extensive passaging in vitro results in the accumulation of mutations, including deletions that result in loss of gene function. Here, we review various comparative analyses of the poxviruses including gene prediction, gene conservation and function, genome organization, and poxvirus taxonomy and evolution.

Introduction

The Poxviridae are best known for two member viruses—Variola virus (VARV) and Vaccinia virus (VACV). VARV is the causative agent of smallpox, a disease that ravaged the human population until its eradication in 1977 by a worldwide vaccination campaign that employed the closely related VACV, which provides effective and long-lasting immunity (Bazin, 2000, Bray and Buller, 2004). The only other human poxvirus pathogens are Molluscum contagiosum virus (MOCV; Hanson and Diven, 2003), which produces relatively benign wart-like lesions, and Monkeypox virus (MPXV), which may produce a smallpox-like disease after rare zoonotic infections (Chen et al., 2005, Edghill-Smith et al., 2005, Hammarlund et al., 2005, Reynolds et al., 2004). Although poxviruses have been studied intensively for many years and smallpox vaccination began more than 200 years ago, much of the life cycle is poorly understood. Owing to fears of reintroduction of smallpox by accidental release or its use as a biological weapon (Mahy, 2003), there has been a recent resurgence in poxvirus research, especially in the areas of vaccine and anti-viral drug design. To support these research programs, the NIH (USA) has funded the development of a Poxvirus Bioinformatics Resource (www.poxvirus.org). More recently, the authors were funded to expand this resource and also to include 6 more virus families (www.biovirus.org). This new Viral Bioinformatics Resource Center (VBRC) offers a variety of tools that make it especially valuable to researchers interested in comparative genomics of viruses; most of the results presented in this review were generated using the data and tools available at the VBRC. One of the most important aspects of the data stored in the VBRC is that it is manually curated, providing users with a high quality data set with which to work. This curation is performed on several levels: (1) newly discovered genes are annotated in all older genomes; (2) orthologous virus genes are clustered, by BLASTP and also manually, into families; (3) a knowledge database is being created to store empirical biological data as well as information on the availability of viruses, clones, mutants, antibodies, etc. The researcher also has a choice of 2 routes to essentially a single set of data: (1) using a web-based set of tools; or (2) using a set of platform-independent Java client-server programs that offer utilities that cannot be provided via HTML interfaces (Fig. 1).