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cooperative conformational changes within Env glycoprotein, and cross-talk
between Env on the viral surfaces. In the case of the retroviruses, this evidence
suggests that virus binding to receptors does not directly induce irreversible
structural changes in SU-TM complexes as was previously believed. Rather, it
implies that the binding to receptors induces SU-SU interactions that are pre-
requisites for later steps in a highly coordinated membrane fusion pathway. We
anticipate that similar intermediate steps are likely to be involved in infections by
other groups of retroviruses and perhaps in infections by other membrane-envel-
oped viruses.
Other viruses can be activated by soluble receptors that, by interacting
with the envelope glycoprotein, induce some of the conformational changes
necessary to trigger fusion. This example indicates that binding and fusion steps
can be separated and can take place at different locations. In these cases, MHV,
avian retrovirus ASLV, and the herpes simplex 1 (HSV-1) can infect some cells
that do not harbor binding receptors provided that the soluble form is present in
the infection media (the soluble CEACAM1 receptor for MHVR, the soluble
Tva receptor for ASLV, and the soluble nectin-1 for HSV-1; Kwon
et al
., 2006;
Matsuyama and Taguchi, 2002; Mothes
et al
., 2000).
IV. BASIC AND TRANSLATIONAL RESEARCH EXPLOITING
ENTRY PROPERTIES OF VIRUSES
A. Tropism properties and use of pseudoparticles in gene therapy
Vectors derived from retroviruses such as lentiviruses and oncoretroviruses are
probably among the most suitable tools to achieve long-term gene transfer, since
they allow stable integration of a transgene and its propagation in daughter cells.
Lentiviral vectors should be the preferred gene-delivery vehicles over vectors
derived from oncoretroviruses (MLV) since, in contrast to the latter, they can
transduce nonproliferating target cells. Moreover, lentiviral vectors that have
the capacity to deliver transgenes into specific tissues are expected to be of great
value for various gene transfer approaches
in vivo
(Frecha
et al
., 2008b).
To achieve such
gene transfer, innovative approaches have been devel-
oped to upgrade lentiviral vectors for tissue or cell targeting and which have
potential for
in vivo
gene delivery. One strategy is to develop vectors that harbor
EnvGP with selective tropisms. Vectors derived from retroviruses offer particu-
larly flexible properties in gene transfer applications, given the numerous possible
associations of various viral surface glycoproteins (determining cell tropism) with
viral cores. Selective tropisms were achieved by taking advantage of the natural
tropisms of EnvGP from other membrane-enveloped viruses. For instance, the
use of surface glycoproteins derived from viruses that cause lung infection and
in vivo
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