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Another challenge will be the identification of the cognate cellular
receptors. Identification of all the cellular receptors for human viruses would be
an important contribution to our understanding of virus tropism and pathogene-
sis. Once known, the role of receptors in entry, as a specific or nonspecific
binding factor, or as receptors needed for conformational changes, or for routing
the virus to the right compartment, will have to be established. Moreover, for
most viruses, the EnvGP appear to function in an autonomous manner and can
permit fusion without a requirement for receptors at acidic pH. Thus, the role of
varied receptors remains enigmatic for many viruses. It is difficult to predict the
roles of a receptor in fusion, sorting and routing the virus toward a particular
favorable compartment in the pursuit of the infectious cycle based upon its
family and its structure. The activation process of EnvGP and the postbinding
events are early steps that are crucial to understand, as they could provide targets
for the development of therapeutics. The better understanding of the envelope-
receptor interaction also raises hopes for the possibility of designing entry
machines that can deliver genes and other molecules to any cell of choice.
Recently, the use of whole genome siRNA screen has become more and
more widely used for different viruses in order to identified factors important for
entry. It should drastically increase our knowledge of the factors necessary for
entry of viruses. Similarly, many high-throughput interactome studies will iden-
tify cellular proteins interacting with the different viral components. Altogether,
the comparison of all these high-throughput screens should help us to identify
cellular proteins and pathways common to different viruses which may help, with
rational structure/mechanism-based design of entry inhibitors, to develop inhi-
bitors that cross-react with different pathogens. In a similar fashion, the design of
vaccine immunogens that are capable of eliciting potent, broadly neutralizing
antibodies of known epitopes, is expected to contribute toward the development
of vaccines. In parallel, the development of panels of human monoclonal anti-
bodies against every entry-related protein from all pathogenic human viruses
could accelerate our understanding of entry mechanisms and help to fight viral
diseases. If research continues at the present pace, most of these goals could be
accomplished within the next few decades.
Acknowledgments
Our research is supported by INSERM, ENS Lyon, CNRS, and UCB Lyon-I and by grants from the
European Union (LSHB-CT-2004-005246 “COMPUVAC”), the European Research Council (ERC
Advanced Grant to FLC No. 233130 “HEPCENT”), the Agence Nationale de Recherches sur le
SIDA et les Hepatites Virales (ANRS), and the FINOVI foundation. We thank Sarah Kabani for
helpful comments on this chapter. We apologize to the many authors of important original contribu-
tions that were not directly cited. Lastly, we thank the past and present members of our laboratory for
their many experimental and intellectual contributions.
