Lipid Membranes in Poxvirus Replication

The poxviruses are a family of large, complex, enveloped DNA viruses that infect a variety of vertebrate and invertebrate hosts. Poxviruses are of significance both medically and scientifically due to their wide distribution, pathogenicity, and cytoplasmic replicative life cycle. Several prominent members, including variola virus (causative agent of smallpox), molluscum contagiosum virus (cause of a common skin infection of young children and immunosuppressed adults) and monkeypox virus (agent of a smallpox-like disease in parts of Africa), are of considerable concern for public health and biodefence. The prototypic and most studied poxvirus – vaccinia virus (VACV) – serves as an effective smallpox vaccine, a platform for recombinant vaccines against other pathogens and an efficient gene expression vector for basic research. Along its approximate 195-kbp double-stranded DNA genome, VACV encodes ~200 proteins, ranging in function from viral RNA and DNA synthesis and virion assembly to modulation of host immune defenses.

The most abundant and simplest infectious form of the poxvirus particle – the mature virion (MV; alternate name: intracellular mature virion [IMV]) – consists of the viral DNA genome encased in a proteinaceous core and an outer lipoprotein membrane with ~60 and ~25 associated viral proteins, respectively. The presence of an inner membrane forming one layer of the core wall has been suggested by cryo-electron tomography but not yet verified by other methods. Following attachment to cell surfaces and fusion with the plasma or endosomal membrane, poxvirus replication is initiated by entry of the viral core into the cytoplasm where all subsequent steps of the life cycle take place. Poxvirus cores harbor the viral DNA-dependent RNA polymerase and transcription factors necessary for expression of early genes, which constitute nearly half of the viral genome and encode proteins needed for DNA replication and intermediate gene transcription as well as a large number of immunomodulators.

Poxvirus particles

Poxviruses exhibit a temporally-regulated gene expression program, i.e., expression of early genes encoding DNA replication and intermediate transcription factors triggers the expression of intermediate genes encoding late gene specific transcription factors. Late gene products primarily consist of structural proteins needed for progeny virion assembly as well as those enzymes destined for incorporation into progeny virions and used for early gene expression during the next round of infection. Assembly of the MV involves more than 80 viral gene products. In addition, during transit through the cytoplasm, a subset of progeny MVs acquires two additional membrane bilayers, one of which is lost during exocytosis of the particle, to yield the less abundant enveloped virion (EV; alternate names: cell-associated enveloped virion [CEV] and extracellular enveloped virion [EEV]). Thus, an EV is essentially an MV with an additional membrane in which at least six unique proteins are associated. EVs are antigenically distinct from MVs and are important for efficient virus dissemination in the infected host and protection against immune defences. In contrast, MVs are released upon cell lysis and may be important for animal-to-animal transmission.

Poxviruses replicate in the cytoplasm of their host cells, where they acquire multiple lipoprotein membranes. Although a proposal that the initial membrane arises de novo has not been substantiated, there is no accepted explanation for its formation from cellular membranes. A subsequent membrane-wrapping step involving modified trans-Golgi or endosomal cisternae results in a particle with three membranes. These wrapped virions traverse the cytoplasm on microtubules; the outermost membrane is lost during exocytosis, the middle one is lost just prior to cell entry, and the remaining membrane fuses with the cell to allow the virus core to enter the cytoplasm and initiate a new infection. This review highlights the role of lipoprotein membranes in poxvirus entry into cells and during the assembly, morphogenesis and release of progeny virions.

Lipid Membranes in Poxvirus Replication. Viruses 2010 2(4): 972-986; doi:10.3390/v2040972

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