Viral Envelope Glycoprotein Studies: A Review

Human emerging virus

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With the rapidly changing environment and climate and changed human demographics viruses are emerging rapidly with more adapting capabilities. It is helping them to infect human population in harsh condition. New strains and pseudotypes of viruses are emerging for occupying expanded ecological niches, thereby producing different disease syndromes in different parts of world, where these viruses are penetrating populations as novel virus. As a result vaccination cannot be possible. Emergent viruses are the viruses which gain the capacity to form new disease causing or pathogenic strain with facilitating pathogenicity in a new niche. Many new viruses are also causing infection, for example Ebola virus, which has been emerged after 2010 (Brault 2007). It is the single member found in the species Zaire ebolavirus, genus Ebolavirus and family Filoviridae. The virus has a negative-sense RNA genome within the tubular viral envelop and their viral envelop is covered with matrix and nucleocapsid components. In different news, it has been revealed that, genetic mutations in Ebola virus strains creating ‘escape variants’, which is blocking the ability of antibody-based treatments of Ebola virus infection (Eurekalert.org 2016).  These escape variants which were rescue of the mutated viruses were isolated during treatment with cocktail antibodies (Eurekalert.org 2016). These new emerged rescue strains were sequenced and two clusters of changes had progressed with permanent change in genome without disrupting the major viral functions along with the ability to cause infection. The neutralization reaction identified that, these mutated strains were using control replication. Therefore, selection of different target domains while making therapeutic cocktails is important for minimizing viral escape (Holmes 2013).

Corona viruses belong  to two subfamilies including Coronavirinae and Torovirinae, in the family Coronaviridae, in the order Nidovirales. Under electron microscope the virus is seen to be with a fringe of large, bulbos surface projections, which creates an image of royal crown. These viral projections known as viral spikes determine the host tropism. It consists of a positive single-stranded RNA genome within a nucleocapsid of helical symmetry (Holmes 2013). This virus causes SARS with infection in upper and lower respiratory tract of human. There are five different corona virus strains. Three corona virus species found co-circulating in Camels in Saudi Arabia. After the SARS outbreaks, virologists has been reviewed their interest in corona virus. Till 2000s, only the two strains HCoV-229E and HCoV-OC43 were known for corona virus. A third stain was discovered, SARS-CoV, which infects human. After 2004, three research labs reported the fourth human corona virus independently, as NL63, NL and New Haven corona virus. In early 2005, fifth human infecting strain was discovered in patients suffering from pneumonia and named Human corona virus HKU1 (Liu et al. 2011). In September 2012, the novel sixth strain was identified, which is officially now known as the Middle East respiratory syndrome corona virus (MERS-CoV). This strain of corona virus promotes severe respiratory infection with shock, acute kidney injury and coagulopathy. Recent studies have been identified MERS-CoV infection associated with neurologic symptoms including altered level of consciousness along with coma, ataxia and focal motor deficit. Bilateral hyperintense lesions on the white matter and subcortical areas of frontal, temporal, parietal lobes, basal ganglia and corpus callosum were identified with gadolinium enhancement (Eurekalert.org 2016). Therefore, besides the acute respiratory syndromes, CNS involvement should be considered with better extent and this area needs more research.

Viral glycoproteins

The Ebola virus (EBOV) contains glycoprotein, which are important for - its attachment and entry into the host organism. It has been revealed that, Ebola virus glycoprotein (GP) is the only viral protein, which is found in a mature Ebola virion; it indicates that, this protein is important for the attachment of the viral particle to the host during entry (Eurekalert.org 2016). However, expression of GP includes dramatic morphological changes within cells which include cell rounding and detachment. It can be identified as the cytopathological changes in the Ebola virus affected cells. Joseph (2010) focused on the mucin domain, which is the highly glycosylated domains in the Ebola GP protein. The study focused on the mechanisms of cytopathological changes created by the viral GP within the affected cells. The cell-biological approaches revealed that, the mucin domain forms a glycan shield on the plasma membrane, which disrupt the function of host proteins, which are in the vicinity of the viral GP. It also revealed that, the GP-mediated shielding of the MHCI complex at the host cell surface does not provide stimuli for the activation of the CD 8+ T cells (Brault 2007). In addition, it was also found that, GP of Ebola virus shielded its own epitopes by steric hindrance at the cell surface, thereby blocks the antigen binding on these epitopes. Finally, the novel way of evading host defence was discovered in this study (Dolnik et al. 2004).

In the case of Corona virus glycoprotein, it is known as the S glycoprotein. This glycoprotein project from the nucleocapsid as viral projections or spikes. This glycoprotein spikes are type I glycoprotein. This glycoprotein is the main target of vaccines against corona virus-related respiratory tract disease. The corona virus spike glycoprotein has major roles in tissue tropism determination, cell-to-cell spread and viral entry (Moore et al. 2004). Additionally, the HE glycoproteins are the second type of smaller spikes, which are found on type II corona virus, which shows the hemagglutinating and esterase activities, it also show similarity with the influenza C virus’s hemaglutinin-esterase fusion protein. The emergence of novel strains of the virus enhanced the potential of the vaccine development with more innovation. The pandemic in 2003 for SARS-CoV reinforced virologists to focus on this virus-related vaccination (Wright et al. 2008). A group of scientist developed the recombinant SARS virus-like particles (VLP) vaccine. This vaccine was created by combining the SARS spike (S) glycoprotein and the influenza M1 proteins, which was expressed in the baculovirus insect cell expression system (Perera et al. 2013). These chimeric SARS VLPs have the similar sized morphology like the wild type glycoprotein. With the help of mouse lethal challenge model the SARS VLP vaccine’s immunogenicity and protective efficacy were measured. The result showed complete protection of mice from death. SARS-CoV VLPs are highly immunogenic and induce the production of neutralizing antibodies, thereby providing protection against lethal challenge (Voynov and Caravella 2012).

Pseudotyped viruses

The psedotyped viruses are the resultant viral particles after viral pseudotyping. These viruses are mainly related to the production of viral vectors. The pseudotyping is the method for production of viral vectors or recombinant viruses. In this process the wild type viruses or viral parts are combined with the foreign envelop proteins. In these pseudotyped virus particles, the foreign viral particles are used for altering host tropism. It enhances or reduces the stability of the viral particles (Brault 2007). In addition, the pseudotyped particles do not carry genetic materials, so cannot spread infection or produce the recombinant viral envelop proteins in the successive generations. Therefore, the phenotypic changes carried to the next generations. The pseudotyped viral vectors are used for identification of viral entry and used in antibody production against the viral antigens. A study revealed that infection of receptor-bearing cells is mediated by the spike (S) glycoprotein of the coronas viruses (Struck et al. 2012). Pseudotyping helps to determine attachment sites. It has revealed in the studies that, the receptors are specified and shows angiotensin-converting enzyme 2 (ACE2) activities. Struck et al. (2012) showed that, pseudotyped viral particles with the combination of SIV and murine leukemia virus along with SARS-CoV S glycoprotein are efficient to infect the HEK293T cells, which expresses ACE2 enzyme in a stable manner. Here the pseudotyping helped to reveal that, in the recombinant viral particle, the entry of the viral particle is mediated by the S-glycoprotein of the SARS-CoV virus, whose entire cytoplasmic domain was truncated and altered with the HIV typer 1 envelop glycoprotein (Weiss and Navas-Martin 2005). Therefore, by the help of S-protein-pseudotypes SIV, it was revealed in this study that, the enzymatic activity of ACE2 has no contribution in the infection mediated by S-glycoprotein of SARS-CoV. In addition, it was shown that, catalytically inactive ACE2 enzyme blocks the infection by S-protein-SIV and wildtype SARS-CoV. Therefore, the pseudotyping can be used in therapeutic intervention of viral infection.

Reference List

Brault, A. (2007). Emerging Viruses in Human Populations. Emerg. Infect. Dis., 13(12), pp.1972-1973.

Dolnik, O., Volchkova, V., Garten, W., Carbonnelle, C., Becker, S., Kahnt, J., Straher, U., Klenk, H. and Volchkov, V. (2004). Ectodomain shedding of the glycoprotein GP of Ebola virus. EMBO J, 23(10), pp.2175-2184.

Eurekalert.org, (2016). EurekAlert! Science News. [online] Available at: https://www.eurekalert.org/ [Accessed 7 Jan. 2016].

Holmes, E. (2013). What can we predict about viral evolution and emergence?. Current Opinion in Virology, 3(2), pp.180-184.

Joseph R., F. (2010). A study of the Ebola virus glycoprotein: Disruption of host surface protein function and evasion of immune responses. [online] Available at: https://repository.upenn.edu/cgi/viewcontent.cgi?article=1295&context=edissertations [Accessed 7 Jan. 2016].

Liu, Y., Massare, M., Barnard, D., Kort, T., Nathan, M., Wang, L. and Smith, G. (2011). Chimeric severe acute respiratory syndrome coronavirus (SARS-CoV) S glycoprotein and influenza matrix 1 efficiently form virus-like particles (VLPs) that protect mice against challenge with SARS-CoV. Vaccine, 29(38), pp.6606-6613.

Moore, M., Dorfman, T., Li, W., Wong, S., Li, Y., Kuhn, J., Coderre, J., Vasilieva, N., Han, Z., Greenough, T., Farzan, M. and Choe, H. (2004). Retroviruses Pseudotyped with the Severe Acute Respiratory Syndrome Coronavirus Spike Protein Efficiently Infect Cells Expressing Angiotensin-Converting Enzyme 2. Journal of Virology, 78(19), pp.10628-10635.

Perera, R., Wang, P., Gomaa, M., El-Shesheny, R., Kandeil, A., Bagato, O., Siu, L., Shehata, M., Kayed, A., Moatasim, Y., Li, M., Poon, L., Guan, Y., Webby, R., Ali, M., Peiris, J. and Kayali, G. (2013). Seroepidemiology for MERS coronavirus using microneutralisation and pseudoparticle virus neutralisation assays reveal a high prevalence of antibody in dromedary camels in Egypt, June 2013. Eurosurveillance, 18(36), p.20574.

Struck, A., Axmann, M., Pfefferle, S., Drosten, C. and Meyer, B. (2012). A hexapeptide of the receptor-binding domain of SARS corona virus spike protein blocks viral entry into host cells via the human receptor ACE2. Antiviral Research, 94(3), pp.288-296.

Voynov, V. and Caravella, J. (2012). Therapeutic proteins. New York: Humana Press.

Weiss, S. and Navas-Martin, S. (2005). Coronavirus Pathogenesis and the Emerging Pathogen Severe Acute Respiratory Syndrome Coronavirus. Microbiology and Molecular Biology Reviews, 69(4), pp.635-664.

Wright, E., Temperton, N., Marston, D., McElhinney, L., Fooks, A. and Weiss, R. (2008). Investigating antibody neutralization of lyssaviruses using lentiviral pseudotypes: a cross-species comparison. Journal of General Virology, 89(9), pp.2204-2213.