Rewiring cellular networks by members of the Flaviviridae family

Key Points

• Flaviviruses and hepaciviruses share similarities in their fundamental replication mechanisms and strategies to manipulate the host cell, yet important differences exist, likely reflecting the use of distinct host cell pathways.

• RNA replication of Flaviviridae family members occurs in tight association with endoplasmic reticulum-derived membranes, which are reorganized into viral replication organelles. Whereas the morphology and the architecture of these replication organelles are well defined, relatively little is known about the viral and cellular factors orchestrating their biogenesis.

• Protein folding, modification and degradation are essential, tightly regulated cellular processes, and a number of common host factors and pathways that are involved in these processes appear to be exploited by both flaviviruses and hepaciviruses at different steps of their replication cycle. These include heat shock protein 70 (HSP70) network components, the unfolded protein response, the ubiquitin-dependent proteasome system and autophagy.

• Accumulating evidence indicates that lipids and lipid metabolism fulfil essential roles in the life cycle of Flaviviridae viruses. They alter the lipid composition of cellular membranes, serving as scaffold for the assembly of the viral replicase by changing their biophysical properties, such as curvature, permeability and fluidity.

• The identification of host cell pathways and factors commonly used by members of the Flaviviridae family might help in the development of broad-spectrum antiviral drugs that target multiple members of this family and/or other virus families.

• As exemplified by members of the Flaviviridae family, the use of host cell pathways does not follow conventional phylogeny but, rather, reveals unexpected commonalities with distantly related viruses, raising the question of evolutionary relationships between these viruses.

Supplementary information

The online version of this article (doi:10.1038/nrmicro.2017.170) contains supplementary material, which is available to authorized users.

Abstract

In this Review, Bartenschlager and colleagues discuss how Flaviviridaeviruses rewire cellular pathways and co-opt organelles. They compare strategies employed by flaviviruses with those employed by hepaciviruses and discuss the importance of these virus–host interactions in the context of viral replication and antiviral therapies.

Supplementary information

The online version of this article (doi:10.1038/nrmicro.2017.170) contains supplementary material, which is available to authorized users.

Abstract

Members of the Flaviviridae virus family comprise a large group of enveloped viruses with a single-strand RNA genome of positive polarity. Several genera belong to this family, including the Hepacivirus genus, of which hepatitis C virus (HCV) is the prototype member, and the Flavivirus genus, which contains both dengue virus and Zika virus. Viruses of these genera differ in many respects, such as the mode of transmission or the course of infection, which is either predominantly persistent in the case of HCV or acutely self-limiting in the case of flaviviruses. Although the fundamental replication strategy of Flaviviridae members is similar, during the past few years, important differences have been discovered, including the way in which these viruses exploit cellular resources to facilitate viral propagation. These differences might be responsible, at least in part, for the various biological properties of these viruses, thus offering the possibility to learn from comparisons. In this Review, we discuss the current understanding of how Flaviviridae viruses manipulate and usurp cellular pathways in infected cells. Specifically, we focus on comparing strategies employed by flaviviruses with those employed by hepaciviruses, and we discuss the importance of these interactions in the context of viral replication and antiviral therapies.

Supplementary information

The online version of this article (doi:10.1038/nrmicro.2017.170) contains supplementary material, which is available to authorized users.