Common Features of Enveloped Viruses and Implications for Immunogen Design for Next-Generation Vaccines - PubMed (original) (raw)

Class II Viruses: Cryo-EM Structures of Flavivirus, Alphavirus and Phlebovirus Particles (A) The top row shows the organization of an immature flavivirus particle (left, icosahedral non quasi-equivalent lattice with 3 protomers per asymmetric unit, 180 UGP/DGP heterodimers) (PDB

5u4w

), the mature alphavirus (middle, icosahedral T = 4 quasi equivalent lattice, 240 UGP/DGP heterodimers)(PDB

5vU2

) and phlebovirus particles (icosahedral T = 12 quasi-equivalent lattice, i.e., 720 UGP/DGP heterodimers) (PDB

6f9b

) The three structures represented display a similar organization in which the DGP (shown in white, gray and black) makes the lateral contacts between spikes (trimeric in flaviviruses and alphaviruses, hexameric and pentameric in phleboviruses), and the UGP (in various colors) caps the fusion loop of the DGP at the spike apices. The viral membrane is shown in steel-grey (arrows). Left column: Flavivirus particle maturation: Immature flavivirus particles undergo a conformational change in response to exposure to low pH in the Golgi, in which the 60 (prM/E)3 spikes (top panel) reorganize into 90 (prM/E)2 dimers (middle panel) (PDB

3c6R

). In this conformation, prM exposes a cleavage site specific for the cellular furin proteinase. Upon cleavage, the peripheral “pr” domain (red, blue and yellow) stays bound as long as the pH is acidic, but is shed from the particle in the neutral pH external environment. Mature flavivirus particles (bottom left) expose the E protein in a herringbone arrangement, completely covering the viral membrane (PDB

5iz7

). All structures are shown at the same scale (bar bottom left, 10nm). (B) Flavivirus particle heterogeneity (left panel) arising from incomplete furin maturation. In the case of dengue viruses, the conformational change between the top left and middle left panels in (A) is reversible with pH, whereas the one from the middle to the bottom panel is irreversible. Because furin is membrane bound, the particles are often processed only on the side that is closest to the TGN membrane with the opposite side uncleaved. Upon release into the neutral external environment, the non-processed side returns to the immature conformation, whereas the processed side adopts the mature conformation, giving rise to mosaic particles exposing the fusion loop in the immature patches. A representation of a “breathing” mature particle (right) shows an expanded size and exposure of the membrane underneath. These particles also expose epitopes normally buried by dimer contacts on virions. (C) Organization of the flavivirus E dimer as present on mature virions as a representative class II DGP (PDB code

5lbv

). One subunit is rainbow colored along the polypeptide chain (from N to C terminus, as indicated in the color key bar below), the other is gray. The three structured domains DI, DII and DIII are indicated as well as the fusion loop (FL). Sites where disulfide bridges have been engineered to stabilize the dimer in the prefusion conformation are marked (star and arrow). Scale bar (bottom, right): 1 nm.