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In contrast, the fusion of Fig. 4.1 most other viruses depends strictly on
their internalization into one of the numerous endocytic pathways such as the
clathrin-dependent, clathrin-independent, and caveolae-independent, as well as
the macropinocytosis (Vaccinia virus) (Mercer and Helenius, 2008) or the
phagocytose (as recently described for Equine herpesvirus 1 virus (Frampton
et al.
, 2007), although in this case not
resulting in a productive infection; Marsh and Helenius, 2006; Sieczkarski and
Whittaker, 2002; Figure 4.1). As described so far, the enveloped viruses that use
these itineraries have fusion reactions that require exposure to a moderately acid
pH in the different endocytosis vesicles (pH-dependent viruses). Classical exam-
ples of viruses that fuse at low pH with the membrane of endosomes or artificial
membranes in the test tube include the influenza orthomyxovirus, the dengue or
the tick-borne encephalitis (TBEV) flaviviruses, and the Semliki forest alpha-
virus (SFV) (Harrison, 2008; Kielian and Rey, 2006; Roche
, 2007) and the HIV virus (Trujillo
et al.
et al
., 2008;
Weissenhorn
., 2007).
Interestingly, an intermediate mechanism has been described for two
retroviruses, ASLS and JSRV. The proposed mechanism of ASLV virion entry
occurs in two steps involving a receptor-priming step that induces Env confor-
mational changes, thus allowing the Env to become sensitive to the action of
acid pH (Mothes
et al
et al.
, 2000). This hybrid mechanism does not lead to cell-cell
fusion
. JSRV also uses receptor priming for fusion activation of JSRV Env
at a low pH, but the mechanism differs slightly to ASLV, requiring dynamin-
associated endocytosis (Bertrand
in vivo
, 2008).
So far, many different endocytosis pathways have been described
(Marsh and Helenius, 2006; Mercer and Helenius, 2009; Mercer
et al.
., 2010b)
as being used by both pH-dependent and pH-independent viruses. However,
reinvestigations of these entry pathways are clearly needed for many pH-inde-
pendent viruses that were originally thought not to rely on endocytosis. For
example, Nipah paramyxoviruses induce fusion between cells at neutral pH and
were considered as a pH-independent virus not reliant on endocytosis for entry.
However, recently, it was proposed that Nipah viruses (NiVs) use macropinocy-
tosis for entry (Pernet
et al
, 2009). It should be noted that viruses that use a pH-
independent mechanism of activation of EnvGP may still enter the cell by
endocytosis without any imperative requirement for acidification activation of
EnvGP in the endosomes.
Clathrin-dependent endocytosis is the best-characterized pathway of
entry and is the major itinerary of entry for pH-dependent viruses. This process
is initiated by the formation of the characteristic invaginations of membrane,
known as clathrin-coated pits (CCP) (Fig. 4.1). The CCP assembly takes place
on the internal face of the plasma membrane following a signal induced by the
activation of a receptor. This clathrin-dependent method of internalization is
used by the Semliki forest and Sindbis alphaviruses, the rubella rubivirus, and the
et al.
