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.