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      Evolution of Cell Recognition by Viruses: A Source of Biological Novelty with Medical Implications

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          The picture beginning to form from genome analyses of viruses, unicellular organisms, and multicellular organisms is that viruses have shared functional modules with cells. A process of coevolution has probably involved exchanges of genetic information between cells and viruses for long evolutionary periods. From this point of view present-day viruses show flexibility in receptor usage and a capacity to alter through mutation their receptor recognition specificity. It is possible that for the complex DNA viruses, due to a likely limited tolerance to generalized high mutation rates, modifications in receptor specificity will be less frequent than for RNA viruses, albeit with similar biological consequences once they occur. It is found that different receptors, or allelic forms of one receptor, may be used with different efficiency and receptor affinities are probably modified by mutation and selection. Receptor abundance and its affinity for a virus may modulate not only the efficiency of infection, but also the capacity of the virus to diffuse toward other sites of the organism. The chapter concludes that receptors may be shared by different, unrelated viruses and that one virus may use several receptors and may expand its receptor specificity in ways that, at present, are largely unpredictable.

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          Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin.

          Hemagglutinin (HA) is the receptor-binding and membrane fusion glycoprotein of influenza virus and the target for infectivity-neutralizing antibodies. The structures of three conformations of the ectodomain of the 1968 Hong Kong influenza virus HA have been determined by X-ray crystallography: the single-chain precursor, HA0; the metastable neutral-pH conformation found on virus, and the fusion pH-induced conformation. These structures provide a framework for designing and interpreting the results of experiments on the activity of HA in receptor binding, the generation of emerging and reemerging epidemics, and membrane fusion during viral entry. Structures of HA in complex with sialic acid receptor analogs, together with binding experiments, provide details of these low-affinity interactions in terms of the sialic acid substituents recognized and the HA residues involved in recognition. Neutralizing antibody-binding sites surround the receptor-binding pocket on the membrane-distal surface of HA, and the structures of the complexes between neutralizing monoclonal Fabs and HA indicate possible neutralization mechanisms. Cleavage of the biosynthetic precursor HA0 at a prominent loop in its structure primes HA for subsequent activation of membrane fusion at endosomal pH (Figure 1). Priming involves insertion of the fusion peptide into a charged pocket in the precursor; activation requires its extrusion towards the fusion target membrane, as the N terminus of a newly formed trimeric coiled coil, and repositioning of the C-terminal membrane anchor near the fusion peptide at the same end of a rod-shaped molecule. Comparison of this new HA conformation, which has been formed for membrane fusion, with the structures determined for other virus fusion glycoproteins suggests that these molecules are all in the fusion-activated conformation and that the juxtaposition of the membrane anchor and fusion peptide, a recurring feature, is involved in the fusion mechanism. Extension of these comparisons to the soluble N-ethyl-maleimide-sensitive factor attachment protein receptor (SNARE) protein complex of vesicle fusion allows a similar conclusion.
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            Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5.

            A complementary DNA clone has been isolated that encodes a coxsackievirus and adenovirus receptor (CAR). When transfected with CAR complementary DNA, nonpermissive hamster cells became susceptible to coxsackie B virus attachment and infection. Furthermore, consistent with previous studies demonstrating that adenovirus infection depends on attachment of a viral fiber to the target cell, CAR-transfected hamster cells bound adenovirus in a fiber-dependent fashion and showed a 100-fold increase in susceptibility to virus-mediated gene transfer. Identification of CAR as a receptor for these two unrelated and structurally distinct viral pathogens is important for understanding viral pathogenesis and has implications for therapeutic gene delivery with adenovirus vectors.
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              Binding of hepatitis C virus to CD81.

              Chronic hepatitis C virus (HCV) infection occurs in about 3 percent of the world's population and is a major cause of liver disease. HCV infection is also associated with cryoglobulinemia, a B lymphocyte proliferative disorder. Virus tropism is controversial, and the mechanisms of cell entry remain unknown. The HCV envelope protein E2 binds human CD81, a tetraspanin expressed on various cell types including hepatocytes and B lymphocytes. Binding of E2 was mapped to the major extracellular loop of CD81. Recombinant molecules containing this loop bound HCV and antibodies that neutralize HCV infection in vivo inhibited virus binding to CD81 in vitro.
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                Author and article information

                Journal
                Adv Virus Res
                Adv. Virus Res
                Advances in Virus Research
                Elsevier Inc.
                0065-3527
                1557-8399
                7 January 2004
                2003
                7 January 2004
                : 62
                : 19-111
                Affiliations
                []Centro de Biología Molecular “Severo Ochoa” (CSIC-UAM), 28049 Madrid, Spain
                []Centro de Investigación en Sanidad Animal (CISA-INIA), 28130 Madrid, Spain
                []Instituto de Biología Molecular de Barcelona (CSIC), 08034 Barcelona, Spain
                Article
                S0065-3527(03)62002-6
                10.1016/S0065-3527(03)62002-6
                7119103
                14719364
                16fb9fbd-4c2a-4c85-bc2f-143e25d614f2
                Copyright © 2003 Elsevier Inc. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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