Abstract
Viruses, as obligate intracellular parasites, exploit cellular pathways and resources in a variety of fascinating ways. A striking example of this is the remodelling of intracellular membranes into specialized structures that support the replication of positive-sense ssRNA (+RNA) viruses infecting eukaryotes. These distinct forms of virus-induced structures include double-membrane vesicles (DMVs), found during viral infections as diverse and notorious as those of coronaviruses, enteroviruses, noroviruses, or hepatitis C virus. Our understanding of these DMVs has evolved over the past 15 years thanks to advances in imaging techniques and modern molecular biology tools. In this article, we review contemporary understanding of the biogenesis, structure, and function of virus-induced DMVs as well as the open questions posed by these intriguing structures.
Highlights
Positive-sense RNA viruses utilize host membranes to generate viral replication organelles (ROs), inducing either invaginated spherules or double-membrane vesicles (DMVs) to support viral RNA synthesis
Virus-induced DMVs appear to derive from membranes of the secretory pathway and form via several membrane remodelling steps coordinated by specific viral nonstructural proteins and host factors
DMVs are sites of viral RNA (vRNA) replication for hepatitis C virus (HCV) [23], appear to be the major replication platform for coronaviruses [17,22], and a substantial support for vRNA replication in picornaviruses [9,10,24], demonstrating that these structures possess the minimum requirements to serve as replication membranes
Summary
The mechanistic details involved, and even the specific contribution of the ROs to this phenomenon, are unclear; components of the nuclear transport machinery, some of which are found in HCV RO regions [80], appear to play key roles in the observed segregation of immune sensors and ROs. Along similar lines, several studies with different DMV-inducing viruses indicate that (intact) ROs have a vital function in shielding vRNA from RNase access or from immunodetection [21,23,81,82,83] making it plausible that this protective function could serve to conceal viral replication intermediates from cellular sensors. These investigations can be complemented with powerful imaging approaches such as cryoelectron tomography and sub-tomogram averaging, which can be used to reveal details
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