The regulation of disassembly of alphavirus cores

Abstract

Alphaviruses are used as model viruses for structure determination and for analysis of virus entry. They are used also as vectors for protein expression and gene therapy. Virus particles are assembled by budding, using preformed cores and a modified cellular membrane. During entry, alphaviruses release the viral core into the cytoplasm. Cores are disassembled during virus entry and accumulate in the cytoplasm during virus multiplication. The regulation of core disassembly is the subject of this review. A working model compatible with all experimental data is formulated. This model comprises the following steps: (1) The incoming core is present in the cytoplasm in a metastable state, primed for disassembly. A core structure containing the so-called linker region of the core protein in an exposed position susceptible to proteolytic cleavage on the core surface might represent the primed state. (2) The primed core allows access of cellular proteins to the viral genome RNA, e.g. initiation factors of protein synthesis. (3) In a following step, ribosomal 60S subunits bind to the complex and lead to core disassembly with a concomitant transfer of core protein or of core protein fragments to the 28S rRNA. The linker region may be involved in this transfer. (4) During the later stages of virus multiplication, cellular components involved in step (2) and/or in step (3) are inactivated. This inactivation might involve the binding of newly synthesised core protein to 28S rRNA. (5) Unprimed cores, e.g. core particles containing the linker region in an unexposed position, are assembled during virus multiplication. Priming of cores and inactivation of host-cell factors each represent a complete mechanism of regulation of core disassembly. Future experiments will show whether or not both processes are actually used. Since alphaviruses, e.g. Chikungunya virus, Ross River virus, Semliki Forest virus, and Sindbis virus, are human pathogens, these experiments are of practical relevance, since they might identify targets for antiviral chemotherapy.