Mechanisms of viral entry: sneaking in the front door

Abstract

Recent developments in methods to study virus internalisation are providing clearer insights into mechanisms used by viruses to enter host cells. The use of dominant negative constructs, specific inhibitory drugs and RNAi to selectively prevent entry through particular pathways has provided evidence for the clathrin-mediated entry of hepatitis C virus (HCV) as well as the caveolar entry of Simian Virus 40. Moreover, the ability to image and track fluorescent-labelled virus particles in real-time has begun to challenge the classical plasma membrane entry mechanisms described for poliovirus and human immunodeficiency virus. This review will cover both well-documented entry mechanisms as well as more recent discoveries in the entry pathways of enveloped and non-enveloped viruses. This will include viruses which enter the cytosol directly at the plasma membrane and those which enter via endocytosis and traversal of internal membrane barrier(s). Recent developments in imaging and inhibition of entry pathways have provided insights into the ill-defined entry mechanism of HCV, bringing it to the forefront of viral entry research. Finally, as high-affinity receptors often define viral internalisation pathways, and tropism in vivo, host membrane proteins to which viral particles specifically bind will be discussed throughout.

Fig. 1

Conventional understanding of entry pathways for particular viruses. Both HIV and Polio virus have been considered able to directly penetrate the host cell plasma membrane. SV40 and coronavirus 229E have been shown to enter through caveolae, while adenovirus2/5, influenza and HCV can all infect through clathrin-mediated endocytosis. However, as described in the text, recent observations are challenging some of these conclusions

Fig. 2

Caveolar endocytosis of SV40. Fluorescence imaging of red-labelled SV40 (Texas Red) and green-labelled caveolae (Caveolin1-GFP) demonstrates a caveolar entry route for SV40 (adapted from Pelkmans et al. ; reprinted by permission from Macmillan Publishers Ltd., copyright 2001)

Fig. 3

Clathrin-mediated endocytosis of Ad2. Electron microscopy of HeLa cells incubated with Ad2 demonstrates internalisation of virus through clathrin-coated pits into clathrin-coated vesicles (adapted from Meier et al 2002). (© Meier et al., , originally published)

Fig. 4

Clathrin-mediated endocytosis of Influenza. Fluorescence imaging of red-labelled virus (DiD) and YFP-tagged clathrin (shown in green) demonstrates a clathrin-mediated entry route for Influenza (adapted from Rust et al ; reprinted by permission from Macmillan Publishers Ltd., copyright 2004)