Three-Dimensional Architecture and Biogenesis of Membrane Structures Associated with Hepatitis C Virus Replication
Figure 9
Hypothetical models describing the formation of double membrane vesicles and their possible role in viral RNA replication.
(A) By analogy to flaviviruses [9] HCV proteins induce invaginations of the ER membrane. Extensive invagination leads to a local ‘shrinking’ of the ER lumen. This model assumes that enzymatically active HCV replicase (green dots) reside in the lumen of the invagination and remain active as long as the vesicle is linked to the cytosol. Upon closure of the DMV, the replicase would become inactive (grey dots). Alternatively, closed DMVs might be connected to the cytosol via proteinaceous channels. (B) HCV proteins might induce tubulation of ER membranes that undergo secondary invagination and thus double membrane wrapping. These DMVs could initially be open to the cytosol, but might close off as replication/infection progresses. The resulting DMV might stay connected to the ER via a stalk or be released as a ‘free’ DMV (left or right drawing, respectively). (C) Induction of DMVs follows the same pathway as described for panel B, but the viral replicase remains on their cytosolic surface as discussed e.g. for the poliovirus [28], [29]. (D) HCV RNA replication might occur on SMVs in close proximity of DMVs. In this case, DMVs might be an epiphenomenon or serve some other purpose for the HCV replication cycle. For each model, structures identified in the 3D reconstructions are shown next to or below the corresponding schematic drawing. For further details see text.