The virus—receptor interaction is exquisitely specific, and a single amino acid change in the receptor can completely abrogate this activity. Thus, the presence of a specific receptor is often a critical determinant in the species specificity of virus infection, and the cell specificity of receptor expression can be a decisive factor in the disease specificity of a virus. CD4 is a key molecule in immune signaling and is expressed on, among others, helper T cells in all mammals.
AIDS is a result of a slow loss of these cells due to the effects of virus infection.
Despite the widespread distribution of CD4 in mammals, HIV-1 can use only the homolog found in primates for entry. In well-studied cases, such as HIV-1, the binding site used by a virus is in a different portion of the receptor molecule than the site of ligand binding, and mutations in the virus-binding site are likely to be of little consequence to the normal host function.
These properties can set the stage for the same sort of arms race as occurs with restriction factors. Indeed, the first host genetic elements found to affect retrovirus infection were receptor polymorphisms in chickens that prevent infection with avian leukosis viruses ALVs . Corresponding polymorphisms are found in ALV isolates from chickens, which can be divided into subgroups A—E based on receptor usage and related properties .
One of the receptor genes, Tvb , comes in at least four flavors, encoding resistance or sensitivity to subgroups B, D, and E in various combinations . Most chickens are sensitive to B viruses and resistant to E; related birds of other species are uniformly sensitive to E and resistant to B viruses. All infectious endogenous i.
This paradox reflects the inferred arms race initiated by entry of a subgroup E virus into chickens, followed by selection of resistant Tvb alleles, and then by evolution of viruses capable of using either the resistant forms of Tvb or another protein as receptor. A similar sort of evolutionary back and forth is also apparent in the endogenous murine leukemia viruses  as well as some other mammalian retroviruses. Demogines et al. The protein in question is TfR1, the receptor for iron-bound transferrin, which mediates iron uptake into cells.
TfR1 is known to serve as receptor for viruses of three unrelated families: mouse mammary tumor virus MMTV , a retrovirus; several rodent and human arenaviruses, such as Machupo; and parvoviruses, including canine parvovirus. In the latter two cases, evolution of the virus to use TfR1 in a different species has been a critical factor allowing recent spread of the viruses to humans and dogs, respectively. In the Machupo virus, the crystal structure of TfR1 bound to the virus GP1 entry protein reveals that the key binding site is a ridge in the apical portion of the butterfly-shaped receptor dimer  Figure 1.
Other lines of evidence have identified the binding site for MMTV as lying on an external ridge about halfway along the outside edge of the protein. To examine the details of the molecular coevolution of these two virus groups and their receptor, Demogines et al. Remarkably, only six residues exhibited ratios significantly greater than 1, and these mapped exactly to the MMTV and Machupo binding sites previously determined Figure 1. These results provide strong evidence for a back and forth coevolution involving the same housekeeping protein and between two different viruses and their rodent hosts.
Based on the evidence of positive selection for its binding sites, the authors speculate that it may once have had a much larger host range, but has become extinct in most lineages, perhaps by being unable to keep up with the resistant mutations in TfR1. Consistent with this idea, Demogines et al. The dimeric, butterfly-shaped protein TfR1 comprises three domains colored yellow, red, and green in one protomer; the other protomer is shown in cyan. The receptor-binding domain of the Machupo virus GP1 protein purple is shown bound to the TfR1 apical domain.
Reprinted with modification from  , with permission.
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The paper concludes with an intriguing observation and an interesting evolutionary puzzle. Although most South American arenavirus infections occur in rodents, several such viruses are spreading into humans in the same region  , so the authors examined human genome databases, seeking evidence for selection of mutations in TfR1 that might affect the emergence of this virus.
Introduction of this mutation into the human TfR1 gene produces a modest two-fold decrease in its ability to serve as receptor for arenavirus in dog cells, which lack functional arenavirus receptors of their own. Intriguingly, the mutant TfR1 reduces the efficiency of infection of human cells by a small amount, even in the presence of a TfR1 allele that can serve as receptor for the virus.
This observation raises the issue that mutations in virus receptors are expected to be recessive and thus have little or no effect on virus infection when they first arise, limiting the opportunity for positive selection to individuals homozygous for the mutation. Perhaps the expected two-fold reduction in active receptor concentration would provide a measure of protection sufficient to give a selective advantage to individuals carrying such a mutation.
Alternatively, as the authors suggest, if the receptor protein is a multimer dimer, in the case of TfR1 , and all binding sites are essential for virus binding and entry, then such a mutation could be functionally dominant. Abstract All viruses need to bind to specific receptor molecules on the surface of target cells to initiate infection. Host Cell Dependency Factors versus Viral Restriction Factors Recent research on a number of fronts is making clear the remarkable extent to which interactions with infectious agents have shaped the evolution of their hosts.
Host—Virus Interactions Change through Positive Selection A characteristic of restriction factor genes—unlike genes encoding housekeeping functions, which usually evolve under purifying selection—is that they often exhibit periods of positive selection in their evolutionary history  , .
When Host Dependency Proteins become Viral Receptors An exception to the apparent lack of positive selection in dependency factors is the interaction with viruses and their cellular receptors, in which signs of an evolutionary arms race have been apparent from classical genetic studies for many years, and for which a paper published in this issue of PLOS Biology  provides strong support based on elegant phylogenetic and virological evidence. Evidence of the Host Arms Race with Retroviruses The virus—receptor interaction is exquisitely specific, and a single amino acid change in the receptor can completely abrogate this activity.
Download: PPT. References 1. PLoS Pathog 5: e View Article Google Scholar 2. Curr Biol R—R View Article Google Scholar 3. J Biol Chem — Interestingly and of relevance to the potential risk to humans, the chances that avian H5N1 viruses will give rise to a pandemic have been deeply analyzed.
The single mutation QL seems not to play an important role for the switch on receptor recognition by the H5 HA, even though it was paramount for the H2N2 and H3N2 viruses. Despite all the knowledge generated in the last 20 years about the H5N1 viruses, it is still unknown why these viruses have not yet become pandemic to humans. The most recent evidence using the ferret model suggested that for the avian H5N1 virus to become transmissible between humans, several mutations at the HA RBS are required, including those previously described in residues and However, it should be considered that some other internal genes also contribute to host adaptation; for instance, the PB2 gene appears to play a central role in the ability of IAV to replicate in different hosts.
The phenotype of efficient replication in mammalian cells seems to result from an amino acid difference at position amino acid change EK, lysine in human strains and glutamate in avian viruses. Avian influenza infections in humans are not just of H5N1 subtype. Avian viruses of the H7N9 subtype have also become a threat to humans.
These AIV, which are restricted to China, infected humans for the first time in ; since then, a total of laboratory-confirmed cases of human infections including at least deaths have been reported to the World Health Organization.
Animal Viruses: Molecular Biology
Not least important these avian viruses of the H7N7 subtype are also a threat to human health. Worldwide, isolated cases or outbreaks of H7N7 have been reported from the Netherlands and Italy. H7N3 viruses are also associated with conjunctivitis when humans are infected. Historically, these viruses have caused human infection in Italy in , in Canada in , and in England in However, besides the fact that viruses replicate efficiently in the upper and lower respiratory tracts of ferrets including the recent Mexican viruses from human cases, transmission between the ferrets still occurs only by direct contact.
The most recent event of zoonotic infections with influenza viruses of avian origin was reported in companion animals. An AIV of the H7N2 subtype was isolated from a person infected through direct contact with sick domestic cats. Viruses isolated from the person and the cat showed Even though this seems an isolated event of AIV trespassing the human host range, it certainly reminds us the plasticity of the IAV to cross the species barrier.
The human airway epithelium is a complex organ of different cell types and functions, and is also the target by which the influenza viruses gain entry to their hosts and from where they are transmitted onward to a new host. However, binding to the target cell is a limiting step for efficient virus replication in the host, and human influenza viruses are presumably adapted to optimize their interactions with this organ.
Dissecting the receptor-binding phenotype of influenza virus has become a primary task for researchers and world health authorities around the globe. The World Health Organization published a Tool for Influenza Pandemic Risk Assessment for those countries that have experienced human infections with animal influenza viruses. This information can help scientists better understand the risk these viruses pose to human health and can help support development of tools and strategies for prevention and treatment. Comparison of complete amino acid sequences and receptor-binding properties among 13 serotypes of hemagglutinin of influenza A viruses.
The structure and function of the hemagglutinin membrane glycoprotein of influenza virus. Annu Rev Biochem. Avian influenza A viruses differ from human viruses by recognition of sialyloligosaccharides and ganglosides and by a higher conservation of the HA receptor-binding site. Essentials of Glycobiology.
Influenza virus strains selectively recognize sialyloligosaccarides on human respiratory epithelium, the role of the host cell in selection of hemagglutinin receptor specificity. Virus Res. Vet Res. Quail as a potential mixing vessel for the generation of new reassortant influenza A viruses. Vet Microbiol.
Early alterations of the receptor-binding properties of H1, H2 and H3 avian influenza virus hemagglutinins after their introduction into mammals. J Virol. Receptor specificity of influenza A viruses correlates with the agglutination of erythrocytes from different animal species. Sialyloligosaccarides of the respiratory epithelium in the selection of human influenza virus receptor specificity. Acta Histochem Suppl. Effects of egg-adaptation on the receptor binding properties of human influenza A and B viruses.
Receptor-binding properties of modern human influenza viruses primarily isolated in Vero and MDCK cells and chicken embryionated eggs. Sweet spots in functional glycomics. Nat Chem Biol. Printed covalent glycan array for ligand profiling of diverse glycan binding proteins. Glycan microarray analysis of the hemagglutinins from modern and pandemic influenza viruses reveals different receptor specificities. J Mol Biol. Receptor-binding specificity of pandemic influenza A H1N1 virus determined by carbohydrate microarray.
Nat Biotechnol. Human and avian influenza viruses target different cell types in cultures of human airway epithelium.
Infection of human airway epithelium by human and avian strains of influenza A virus. Haemagglutinin mutations responsible for the binding of H5N1 influenza A viruses to human-type receptors. Hemagglutinin residues of recent human A H3N2 influenza viruses that contribute to the inability to agglutinate chicken erythrocytes. Nobusawa E, Ishihara H. Change in receptor-binding specificity of recent human influenza A viruses H3N2 : a single amino acid change in hemagglutinin altered its recognition of sialyloligosaccharides. A single amino acid substitution in influenza virus hemagglutinin changes receptor binding specificity.
A two-amino acid change in the hemagglutinin of the influenza virus abolishes transmission. Scholtissek C. Source for influenza pandemics. Eur J Epidemiol.
Molecular basis for the generation in pigs of influenza A viruses with pandemic potential. Comparison of the receptor binding properties of contemporary swine isolates and early human pandemic H1N1 isolates Novel H1N1. Receptor specificity of subtype H1 influenza A viruses isolated from swine and humans in the United States. Influenza virus receptors in the human airway. Characterization of a human H5N1 influenza A virus isolated in Quasispecies of the DG substitution in the hemagglutinin of pandemic influenza A H1N1 virus from patients with severe disease in Hong Kong, China.
J Infect Dis. Frequency of DG haemagglutinin mutant of pandemic H1N1 pdm09 influenza virus in Tunisia between and Diagn Pathol. Substitutions in position of haemagglutinin of pandemic influenza A H1N1 viruses in Spain. J Clin Virol. Euro Surveill. Virol J. The pandemic H1N1 DG hemagglutinin mutation alters receptor specificity and increases virulence in mice but not in ferrets. PLos One. Virulence-associated substitution DG in the hemagglutinin of pandemic influenza A H1N1 virus affects receptor binding. Clin Microbiol Infect. Polymorphisms at residue of the hemagglutinin of pandemic influenza A H1N1 pdm association of quasispecies to morbidity and mortality in different risk categories.
Amino acid substitution DN from fatal influenza infections affects receptor-binding properties of the influenza A H1N1 pdm09 virus. Evolution of the hemagglutinin protein of the new pandemic H1N1 influenza virus: maintaining optimal receptor binding by compensatory substitutions. Hemagglutinin receptor binding avidity drives influenza A virus antigenic drift. Identification of amino acid substitutions supporting antigenic change in influenza A H1N1 pdm09 viruses. Substitutions near the receptor binding site determine major antigenic change during influenza virus evolution.
Mapping the antigenic and genetic evolution of influenza virus. Evolution of the receptor binding properties of the influenza A H3N2 hemagglutinin. Human H3N2 influenza viruses isolated from to show varying preference for receptor substructures with no apparent consequences for disease or spread. Recent H3N2 viruses have evolved specificity for extended, branched huma-type receptors, confering potential for increased avidity.
Cell Host Microbe. Avian influenza virus isolated from a woman with conjunctivitis. Conjunctivitis in human beings caused by influenza A virus of seals. N Engl J Med. Receptor specificity in human, avian, and equine H2 and H3 influenza virus isolates. Evolution of H5N1 avian influenza viruses in Asia.
Global influenza program surveillance network. Emerg Infect Dis. Toward a unified nomenclature system for highly pathogenic avian influenza virus H5N1. Rapid emergence of highly pathogenic avian influenza subtypes from a subtype H5N1 hemagglutinin variant. Intracontinental and intercontinental dissemination of Asian H5 highly pathogenic avian influenza virus clade 2.
Rev Med Virol. Genesis, evolution and prevalence of H5N6 avian influenza viruses in China.
Human clade 2. Evolution of the receptor binding phenotype of influenza A H5 viruses. X-ray structures of H5 avian and H9 swine influenza virus hemagglutinin bound to avian and human receptor analogs. The index influenza A virus subtype H5N1 isolated from a human in differs in its receptor-binding properties from a virulent avian influenza virus. J Gen Virol. The surface glycoprotein of H5 influenza viruses isolated from humans, chickens, and wild aquatic birds have distinguishable properties.
Molecular characterization of the complete genome of human influenza H5N1 virus isolated from Thailand. Highly pathogenic influenza A H5Nx viruses with altered H5 receptor-binding specificity. Mutations in H5N1 influenza virus hemagglutinin that confer binding to human tracheal airway epithelium. A single amino acid in the PB2 gene of influenza A virus is a determinant of host range. Influenza at the Human-Animal Interface.
Summary and Assessment, 16 June to 25 July Human infection with a novel avian-origin influenza A H7N9 virus. Pathogenesis and transmission of avian influenza A H7N9 virus in ferrets and mice.