Biology Reference
In-Depth Information
We will first introduce envelope architecture and structure of the viral
fusion machineries that have been developed to achieve the fusion and entry
steps. Despite many differences of structure, they share a common refolding
process that activates different fusion domains found in most fusion proteins.
We will then illustrate the different fusion regulation processes that have been
developed by viruses to lead to functional virions, both in terms of cleavage
activation of fusion proteins during exit and in terms of activation during
binding and endocytosis. Despite some differences between distinct players,
some common principles can be proposed for all fusion processes. We will
illustrate the molecular details characterizing the maturation of the different
fusion proteins, defined by the following three characteristics: the cleavage of an
envelope protein precursor, the presence and triggering of the exposition of a
fusion peptide, and an association as a trimeric complex association in its active
fusion conformation. The progression of these structural rearrangements slows
down the kinetic barrier between hemifusion and fusion-pore formation. In a
second part, we will present the different entry pathways and cell proteins that
are used by viruses to infect cells. Viruses have emerged as valuable tools for the
study of endocytic mechanisms. These properties have been crucial for the
development of pseudoparticles for their use in terms of vector for gene therapy
and for their use in terms of tool for receptor cloning, transgenesis, or transduc-
tion. Finally, we will give examples of strategies that have been developed
in vivo
and
to inhibit the entry step of the enveloped viruses which have led, in
the case of HIV, to the development of inhibitors that are used in the clinic.
in vitro
II. ARCHITECTURE AND STRUCTURE OF THE VIRAL
FUSION MACHINERY
A. Membrane fusion according to the stalk-pore model
EnvGP are responsible for bringing the membranes closer, triggering the link and
the destabilization of the outer leaflet, the merging of the whole membrane, and
the opening of a pore through the cell and virus membrane to allow the core to
enter the cytoplasm of the cell. The hypothesis of the pore model in viral
membrane fusion mechanism is supported by experimental results. The first
evidence for a hemifusion intermediate was achieved by studying influenza
virus entry that occurs after the hemagglutinin glycoprotein binding to the
host cell. The substitution of the hemagglutinin transmembrane domain by a
glycosylphosphatidylinositol (GPI) revealed the importance of the transmem-
brane region for the fusion pore opening and expansion. Hemifusion structures
are connections between outer leaflets of apposed membranes, whereas the inner
leaflets remain distinct. This is a transient structure that either dissociates or
