Infection of Cells by Alphaviruses

Abstract

It is widely accepted that alphaviruses enter cells by a process involving endocytosis and low-pH-mediated virus membrane-cell membrane fusion. This model and the data supporting it have received extensive and numerous reviews. The major points presented in support of this model are summarized briefly herein. It is the primary objective of this review to present an alternative mechanism describing the penetration of cells by alphaviruses which does not involve endocytosis or exposure to acid environment. The data supporting this model are summarized in detail.

Alphavirus Genome Delivery Occurs Directly at the Plasma Membrane in a Time- and Temperature-Dependent Process

“…The virus would not encounter this sequence of events during endocytosis by a living cell. The details of these models are described in two recent reviews (3,16). Thus, we have produced a body of data that suggest that acid pH, membrane fusion, and endocytosis are not involved in the alphavirus entry process (described above and reviewed by Brown and Hernandez [16]).…”

“…The details of these models are described in two recent reviews (3,16). Thus, we have produced a body of data that suggest that acid pH, membrane fusion, and endocytosis are not involved in the alphavirus entry process (described above and reviewed by Brown and Hernandez [16]). While these data suggest that a different pathway of entry exists, we have been unable to clearly define that mode of entry.…”

Self-Amplifying mRNA Vaccines

“…It was previously thought that alphaviruses enter cells by receptor-mediated endocytosis, followed by a viral membrane, cell membrane fusion event in the endolysosomes to release the RNA and nucleocapsid into the cell cytosol (Kielian & Rey, 2006). However, a growing body of work challenges this model and demonstrates that alphavirus entry is independent of endocytosis and acidic pH-dependent membrane fusion (reviewed in (Brown & Hernandez, 2012;Vancini, Wang, Ferreira, Hernandez, & Brown, 2013), suggesting that viral entry may also occur directly through the plasma membrane.…”

Structural Differences Observed in Arboviruses of the Alphavirus and Flavivirus Genera

“…Sindbis virus carrying a green fluorescent protein will infect BHK cells at 15°C in the absence of fusion, or endocytosis producing fluorescent cells without return through higher temperatures [ 133 ]. The obvious implication of these data is that studies in which virus has been allowed to attach on ice for one hour during the infection phase may not have synchronized the infection, as proposed in these studies, but rather allowed infectious particles to be internalized [ 122 , 131 , 133 , 165 ], reviewed in [ 165 , 166 ] ( Figure 14 ). However, the effect of 15°C on formation of the replication complex has not been reported for Sindbis virus but it is possible that synchronization occurs at the level of RNA synthesis.…”