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Review
. 2021 Aug 4;10(8):984.
doi: 10.3390/pathogens10080984.

Alphavirus-Induced Membrane Rearrangements during Replication, Assembly, and Budding

Zeinab Elmasri  1   2 , Benjamin L Nasal  2 , Joyce Jose  1   2
Affiliations
Review

Alphavirus-Induced Membrane Rearrangements during Replication, Assembly, and Budding

Zeinab Elmasri et al. Pathogens. .

Abstract

Alphaviruses are arthropod-borne viruses mainly transmitted by hematophagous insects that cause moderate to fatal disease in humans and other animals. Currently, there are no approved vaccines or antivirals to mitigate alphavirus infections. In this review, we summarize the current knowledge of alphavirus-induced structures and their functions in infected cells. Throughout their lifecycle, alphaviruses induce several structural modifications, including replication spherules, type I and type II cytopathic vacuoles, and filopodial extensions. Type I cytopathic vacuoles are replication-induced structures containing replication spherules that are sites of RNA replication on the endosomal and lysosomal limiting membrane. Type II cytopathic vacuoles are assembly induced structures that originate from the Golgi apparatus. Filopodial extensions are induced at the plasma membrane and are involved in budding and cell-to-cell transport of virions. This review provides an overview of the viral and host factors involved in the biogenesis and function of these virus-induced structures. Understanding virus-host interactions in infected cells will lead to the identification of new targets for antiviral discovery.

Keywords: Togaviridae; alphavirus; assembly; budding; cytopathic vacuole; filopodia; nucleocapsid core; replication; spherule.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Alphavirus-induced replication organelles. Alphavirus replication spherules form at the plasma membrane and require the presence of nsP1, nsP2, nsP3, and nsP4. Structural studies proposed that the nsP1 ring complex forms the base of the alphavirus RC and plays a role in membrane curvature. The HVD of nsP3 contains a YXXM motif capable of binding to p85, relieving p110 inhibition. P110 catalyzes the phosphorylation of PIP2, generating PIP3, which can recruit and activate Akt at the plasma membrane. Active Akt promotes spherule internalization from the plasma membrane in an actin-myosin-dependent manner. Endocytic spherule-containing vesicles fuse with late endosomes to form acidic vesicles that traffic to the perinuclear area via microtubules, where they mature to form large CPV-Is. Figure created with BioRender.com.
Figure 2
Figure 2
Structures formed during alphavirus assembly. CPV-IIs originate with variable morphologies from the trans-Golgi network. These structures have multiple NCs associated with them, and some contain tubular formations of glycoprotein spikes. CPV-IIs are presumably trafficked to the plasma membrane to deliver NCs and mature glycoproteins. Alphavirus infection also results in actin-rich filopodial extensions that facilitate budding and cell-to-cell spread. Figure created with BioRender.com.
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