The Virus-Host Interplay: Biogenesis of +RNA Replication Complexes

Abstract

Positive-strand RNA (+RNA) viruses are an important group of human and animal pathogens that have significant global health and economic impacts. Notable members include West Nile virus, Dengue virus, Chikungunya, Severe acute respiratory syndrome (SARS) Coronavirus and enteroviruses of the Picornaviridae family.Unfortunately, prophylactic and therapeutic treatments against these pathogens are limited. +RNA viruses have limited coding capacity and thus rely extensively on host factors for successful infection and propagation. A common feature among these viruses is their ability to dramatically modify cellular membranes to serve as platforms for genome replication and assembly of new virions. These viral replication complexes (VRCs) serve two main functions: To increase replication efficiency by concentrating critical factors and to protect the viral genome from host anti-viral systems. This review summarizes current knowledge of critical host factors recruited to or demonstrated to be involved in the biogenesis and stabilization of +RNA virus VRCs.

Keywords: +RNA viruses; host factors; membranes; replication complexes.

Figure 1

Biogenesis of Viral Replication Complexes (VRCs): Representative diagram of the structure and biogenesis of the VRCs for each family based on electron microscopy from the following references: Poliovirus (PV) [23] Semliki Forest virus (SFV) [24], Dengue virus (DENV) [15], Severe acute respiratory syndrome coronavirus (SARS-CoV) [25]. Diagram not to scale. (A) Formation of the PV VRC: Early in infection single membrane vesicles that contain dsRNA are derived from the ER and Golgi components. Progression of infection results in vesicles wrapping around each other inducing the formation of DMVs; (B) Formation of the DENV VRC: Spherule structures containing dsRNA form on modified rough-ER membranes surrounded by convoluted membranes. Assembly sites form on opposing cisternae where newly formed virions are stored; (C) Formation of SFV VRC: Spherules that contain dsRNA form at the plasma membrane. Internalization of these structures follows the endo-lysosomal pathway resulting in formation of cytopathic vacuoles (CPV); (D) Proposed formation of the SARS-CoV VRC: DMVs containing dsRNA are formed and their outer membranes are continuous with the ER. Convoluted membranes surround the DMVs. Formation of vesicle packets (VPs) is thought to result from DMV fusion. Newly formed virions are associated with these structures.