scholarly journals The Development of SARS-CoV-2 Variants: The Gene Makes the Disease

2021 ◽  
Vol 9 (4) ◽  
pp. 58
Author(s):  
Raquel Perez-Gomez
Keyword(s):  
Protein Function ◽  
Immune Escape ◽  
Current Knowledge ◽  
Viral Fitness ◽  
High Rate ◽  
Spike Protein ◽  
Cell Contact ◽  
Genetic Profile ◽  
Level Of Concern ◽  
The Impact

A novel coronavirus (SARS-CoV-2) emerged towards the end of 2019 that caused a severe respiratory disease in humans called COVID-19. It led to a pandemic with a high rate of morbidity and mortality that is ongoing and threatening humankind. Most of the mutations occurring in SARS-CoV-2 are synonymous or deleterious, but a few of them produce improved viral functions. The first known mutation associated with higher transmissibility, D614G, was detected in early 2020. Since then, the virus has evolved; new mutations have occurred, and many variants have been described. Depending on the genes affected and the location of the mutations, they could provide altered infectivity, transmissibility, or immune escape. To date, mutations that cause variations in the SARS-CoV-2 spike protein have been among the most studied because of the protein’s role in the initial virus–cell contact and because it is the most variable region in the virus genome. Some concerning mutations associated with an impact on viral fitness have been described in the Spike protein, such as D614G, N501Y, E484K, K417N/T, L452R, and P681R, among others. To understand the impact of the infectivity and antigenicity of the virus, the mutation landscape of SARS-CoV-2 has been under constant global scrutiny. The virus variants are defined according to their origin, their genetic profile (some characteristic mutations prevalent in the lineage), and the severity of the disease they produce, which determines the level of concern. If they increase fitness, new variants can outcompete others in the population. The Alpha variant was more transmissible than previous versions and quickly spread globally. The Beta and Gamma variants accumulated mutations that partially escape the immune defenses and affect the effectiveness of vaccines. Nowadays, the Delta variant, identified around March 2021, has spread and displaced the other variants, becoming the most concerning of all lineages that have emerged. The Delta variant has a particular genetic profile, bearing unique mutations, such as T478K in the spike protein and M203R in the nucleocapsid. This review summarizes the current knowledge of the different mutations that have appeared in SARS-CoV-2, mainly on the spike protein. It analyzes their impact on the protein function and, subsequently, on the level of concern of different variants and their importance in the ongoing pandemic.

scholarly journals Stability of the Influenza Virus Hemagglutinin Protein Correlates with Evolutionary Dynamics

mSphere ◽  
2018 ◽  
Vol 3 (1) ◽  
Author(s):  
Eili Y. Klein ◽  
Deena Blumenkrantz ◽  
Adrian Serohijos ◽  
Eugene Shakhnovich ◽  
Jeong-Mo Choi ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Protein Stability ◽  
Evolutionary Dynamics ◽  
Immune Escape ◽  
Antigenic Site ◽  
Viral Fitness ◽  
Influenza Virus Hemagglutinin ◽  
Hemagglutinin Protein ◽  
Ha Protein ◽  
The Impact

ABSTRACTProtein thermodynamics are an integral determinant of viral fitness and one of the major drivers of protein evolution. Mutations in the influenza A virus (IAV) hemagglutinin (HA) protein can eliminate neutralizing antibody binding to mediate escape from preexisting antiviral immunity. Prior research on the IAV nucleoprotein suggests that protein stability may constrain seasonal IAV evolution; however, the role of stability in shaping the evolutionary dynamics of the HA protein has not been explored. We used the full coding sequence of 9,797 H1N1pdm09 HA sequences and 16,716 human seasonal H3N2 HA sequences to computationally estimate relative changes in the thermal stability of the HA protein between 2009 and 2016. Phylogenetic methods were used to characterize how stability differences impacted the evolutionary dynamics of the virus. We found that pandemic H1N1 IAV strains split into two lineages that had different relative HA protein stabilities and that later variants were descended from the higher-stability lineage. Analysis of the mutations associated with the selective sweep of the higher-stability lineage found that they were characterized by the early appearance of highly stabilizing mutations, the earliest of which was not located in a known antigenic site. Experimental evidence further suggested that H1N1 HA stability may be correlated within vitrovirus production and infection. A similar analysis of H3N2 strains found that surviving lineages were also largely descended from viruses predicted to encode more-stable HA proteins. Our results suggest that HA protein stability likely plays a significant role in the persistence of different IAV lineages.IMPORTANCEOne of the constraints on fast-evolving viruses, such as influenza virus, is protein stability, or how strongly the folded protein holds together. Despite the importance of this protein property, there has been limited investigation of the impact of the stability of the influenza virus hemagglutinin protein—the primary antibody target of the immune system—on its evolution. Using a combination of computational estimates of stability and experiments, our analysis found that viruses with more-stable hemagglutinin proteins were associated with long-term persistence in the population. There are two potential reasons for the observed persistence. One is that more-stable proteins tolerate destabilizing mutations that less-stable proteins could not, thus increasing opportunities for immune escape. The second is that greater stability increases the fitness of the virus through increased production of infectious particles. Further research on the relative importance of these mechanisms could help inform the annual influenza vaccine composition decision process.

scholarly journals On the biomechanical properties of osteosarcoma cells and their environment

2019 ◽  
Vol 63 (1-2) ◽  
pp. 1-8 ◽  
Author(s):  
Daniel A. Müller ◽  
Unai Silvan
Keyword(s):  
Current Knowledge ◽  
Osteogenic Sarcoma ◽  
Cell Types ◽  
Biomechanical Properties ◽  
High Rate ◽  
Osteosarcoma Cells ◽  
High Tendency ◽  
Cell Responses ◽  
Frequent Use ◽  
The Impact

Although rare among the general population, bone malignancies have a high rate of incidence among children and adolescents and are associated with high mortality rates. Osteosarcoma (also known as osteogenic sarcoma) is the most frequent primary cancer of bone and shows a high tendency to metastasize to the lung. Despite the frequent use of osteosarcoma-derived cell lines in basic biomechanical research and for the evaluation of cell responses to new biomaterials, the mechanical phenotype and the differences between osteosarcoma cells and related cell types, such as mesenchymal cells, osteoblasts and osteocytes, remain largely unknown. In the present review we summarize current knowledge of the biophysical and mechanical properties of the niche of primary osteosarcomas and of the malignant cells, and discuss the impact of these features on the progression of malignancy.

scholarly journals Immune Escape Variants of H9N2 Influenza Viruses Containing Deletions at the Hemagglutinin Receptor Binding Site Retain Fitness In Vivo and Display Enhanced Zoonotic Characteristics

2017 ◽  
Vol 91 (14) ◽  
Author(s):  
Thomas P. Peacock ◽  
Donald J. Benton ◽  
Joe James ◽  
Jean-Remy Sadeyen ◽  
Pengxiang Chang ◽  
...  
Keyword(s):  
Avian Influenza ◽  
Receptor Binding ◽  
Immune Escape ◽  
Influenza Pandemic ◽  
Influenza Viruses ◽  
Viral Fitness ◽  
Antigenic Drift ◽  
Zoonotic Infection ◽  
Avian Influenza Viruses ◽  
The Impact

ABSTRACT H9N2 avian influenza viruses are enzootic in poultry across Asia and North Africa, where they pose a threat to human health as both zoonotic agents and potential pandemic candidates. Poultry vaccination against H9N2 viruses has been employed in many regions; however, vaccine effectiveness is frequently compromised due to antigenic drift arising from amino acid substitutions in the major influenza virus antigen hemagglutinin (HA). Using selection with HA-specific monoclonal antibodies, we previously identified H9N2 antibody escape mutants that contained deletions of amino acids in the 220 loop of the HA receptor binding sites (RBSs). Here we analyzed the impact of these deletions on virus zoonotic infection characteristics and fitness. We demonstrated that mutant viruses with RBS deletions are able to escape polyclonal antiserum binding and are able to infect and be transmitted between chickens. We showed that the deletion mutants have increased binding to human-like receptors and greater replication in primary human airway cells; however, the mutant HAs also displayed reduced pH and thermal stability. In summary, we infer that variant influenza viruses with deletions in the 220 loop could arise in the field due to immune selection pressure; however, due to reduced HA stability, we conclude that these viruses are unlikely to be transmitted from human to human by the airborne route, a prerequisite for pandemic emergence. Our findings underscore the complex interplay between antigenic drift and viral fitness for avian influenza viruses as well as the challenges of predicting which viral variants may pose the greatest threats for zoonotic and pandemic emergence. IMPORTANCE Avian influenza viruses, such as H9N2, cause disease in poultry as well as occasionally infecting humans and are therefore considered viruses with pandemic potential. Many countries have introduced vaccination of poultry to try to control the disease burden; however, influenza viruses are able to rapidly evolve to escape immune pressure in a process known as “antigenic drift.” Previously, we experimentally generated antigenic-drift variants in the laboratory, and here, we test our “drifted” viruses to assess their zoonotic infection characteristics and transmissibility in chickens. We found that the drifted viruses were able to infect and be transmitted between chickens and showed increased binding to human-like receptors. However, the drift mutant viruses displayed reduced stability, and we predict that they are unlikely to be transmitted from human to human and cause an influenza pandemic. These results demonstrate the complex relationship between antigenic drift and the potential of avian influenza viruses to infect humans.

scholarly journals Impact of the Double Mutants on Spike Protein of SARS-CoV-2 B.1.617 Lineage to the Human ACE2 Receptor Binding: A Structural Insight

Viruses ◽  
2021 ◽  
Vol 13 (11) ◽  
pp. 2295
Author(s):  
Mohd Imran Khan ◽  
Mohammad Hassan Baig ◽  
Tanmoy Mondal ◽  
Mohammed Alorabi ◽  
Tanuj Sharma ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Receptor Binding ◽  
Immune Escape ◽  
Principal Component ◽  
Spike Protein ◽  
Human Host ◽  
Recent Emergence ◽  
Novel Variants ◽  
Structural Insight ◽  
The Impact

The recent emergence of novel SARS-CoV-2 variants has threatened the efforts to contain the COVID-19 pandemic. The emergence of these “variants of concern” has increased viral transmissibility or immune escape and has supplanted the ancestral strains. The novel variants harbored by the B.1.617 lineage (Kappa and Delta) carry mutations within the receptor-binding domain of spike (S) protein (L452R + E484Q and L452R + T478K), the region binding to the host receptor. The double mutations carried by these novel variants are primarily responsible for an upsurge number of COVID-19 cases in India. In this study, we thoroughly investigated the impact of these double mutations on the binding capability to the human host receptor. We performed several structural analyses and found that the studied double mutations increase the binding affinity of the spike protein to the human host receptor (ACE2). Furthermore, our study showed that these double mutants might be a dominant contributor enhancing the receptor-binding affinity of SARS-CoV-2 and consequently making it more stable. We also investigated the impact of these mutations on the binding affinity of two monoclonal antibodies (Abs) (2-15 and LY-CoV555) and found that the presence of the double mutations also hinders its binding with the studied Abs. The principal component analysis, free energy landscape, intermolecular interaction, and other investigations provided a deeper structural insight to better understand the molecular mechanism responsible for increased viral transmissibility of these variants.

scholarly journals Transmission of HIV-1 Gag immune escape mutations is associated with reduced viral load in linked recipients

2008 ◽  
Vol 205 (5) ◽  
pp. 1009-1017 ◽  
Author(s):  
Paul A. Goepfert ◽  
Wendy Lumm ◽  
Paul Farmer ◽  
Philippa Matthews ◽  
Andrew Prendergast ◽  
...  
Keyword(s):  
Viral Load ◽  
Immune Escape ◽  
Cytotoxic T Lymphocyte ◽  
Human Leukocyte ◽  
Viral Fitness ◽  
Leukocyte Antigen ◽  
Ctl Escape ◽  
The Impact ◽  
Hiv 1

In a study of 114 epidemiologically linked Zambian transmission pairs, we evaluated the impact of human leukocyte antigen class I (HLA-I)–associated amino acid polymorphisms, presumed to reflect cytotoxic T lymphocyte (CTL) escape in Gag and Nef of the virus transmitted from the chronically infected donor, on the plasma viral load (VL) in matched recipients 6 mo after infection. CTL escape mutations in Gag and Nef were seen in the donors, which were subsequently transmitted to recipients, largely unchanged soon after infection. We observed a significant correlation between the number of Gag escape mutations targeted by specific HLA-B allele–restricted CTLs and reduced VLs in the recipients. This negative correlation was most evident in newly infected individuals, whose HLA alleles were unable to effectively target Gag and select for CTL escape mutations in this gene. Nef mutations in the donor had no impact on VL in the recipient. Thus, broad Gag-specific CTL responses capable of driving virus escape in the donor may be of clinical benefit to both the donor and recipient. In addition to their direct implications for HIV-1 vaccine design, these data suggest that CTL-induced viral polymorphisms and their associated in vivo viral fitness costs could have a significant impact on HIV-1 pathogenesis.

scholarly journals Mutational hotspot in the SARS-CoV-2 Spike protein N-terminal domain conferring immune escape potential

2021 ◽  
Author(s):  
Slawomir Kubik ◽  
Nils Arrigo ◽  
Jaume Bonet ◽  
Zhenyu Xu
Keyword(s):  
Early Identification ◽  
High Frequency ◽  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Spike Protein ◽  
Striking Increase ◽  
Terminal Domain ◽  
Critical Residue ◽  
Optimal Efficiency ◽  
The Impact

ABSTRACTGlobal efforts are being taken to monitor the evolution of SARS-CoV-2, aiming at early identification of mutations with the potential of increasing viral infectivity or virulence. We report a striking increase in the frequency of recruitment of diverse substitutions at a critical residue (W152), positioned in the N-terminal domain (NTD) of the Spike protein, observed repeatedly across independent phylogenetic and geographical contexts. We investigate the impact these mutations might have on the evasion of neutralizing antibodies. Finally, we uncover that NTD is a region exhibiting particularly high frequency of mutation recruitments, suggesting an evolutionary path on which the virus maintains optimal efficiency of ACE2 binding combined with the flexibility facilitating the immune escape.

scholarly journals Infectivity and immune escape of the new SARS-CoV-2 variant of interest Lambda

2021 ◽  
Author(s):  
M&oacutenica L. Acevedo ◽  
Luis Alonso-Palomares ◽  
Andr&eacutes Bustamante ◽  
Aldo Gaggero ◽  
Fabio Paredes ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Neutralization Assay ◽  
Spike Protein ◽  
Pseudotyped Virus ◽  
South American ◽  
Virus Neutralization Assay ◽  
Alpha Variant ◽  
Vaccination Campaigns ◽  
The Impact

Background: The newly described SARS-CoV-2 lineage C.37 was recently classified as a variant of interest by the WHO (Lambda variant) based on its high circulation rates in South American countries and the presence of critical mutations in the spike protein. The impact of such mutations in infectivity and immune escape from neutralizing antibodies are entirely unknown. Methods: We performed a pseudotyped virus neutralization assay and determined the impact of the Lambda variant on infectivity and immune escape using plasma samples from healthcare workers (HCW) from two centers in Santiago, Chile who received the two-doses scheme of the inactivated virus vaccine CoronaVac. Results: We observed an increased infectivity mediated by the Lambda spike protein that was even higher than that of the D614G (lineage B) or the Alpha and Gamma variants. Compared to the Wild type (lineage A), neutralization was decreased by 3.05-fold for the Lambda variant while it was 2.33-fold for the Gamma variant and 2.03-fold for the Alpha variant. Conclusions: Our results indicate that mutations present in the spike protein of the Lambda variant of interest confer increased infectivity and immune escape from neutralizing antibodies elicited by CoronaVac. These data reinforce the idea that massive vaccination campaigns in countries with high SARS-CoV-2 circulation must be accompanied by strict genomic surveillance allowing the identification of new isolates carrying spike mutations and immunology studies aimed to determine the impact of these mutations in immune escape and vaccines breakthrough.

scholarly journals Immunity against Lagovirus europaeus and the Impact of the Immunological Studies on Vaccination

Vaccines ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 255
Author(s):  
Claudia Müller ◽  
Rafał Hrynkiewicz ◽  
Dominika Bębnowska ◽  
Jaime Maldonado ◽  
Massimiliano Baratelli ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Current Knowledge ◽  
Hemorrhagic Fever ◽  
High Rate ◽  
Rabbit Hemorrhagic Disease Virus ◽  
Hemorrhagic Disease ◽  
Rabbit Hemorrhagic Disease ◽  
Intravascular Coagulopathy ◽  
The Impact ◽  
Very High

In the early 1980s, a highly contagious viral hemorrhagic fever in rabbits (Oryctolagus cuniculus) emerged, causing a very high rate of mortality in these animals. Since the initial occurrence of the rabbit hemorrhagic disease virus (RHDV), several hundred million rabbits have died after infection. The emergence of genetically-different virus variants (RHDV GI.1 and GI.2) indicated the very high variability of RHDV. Moreover, with these variants, the host range broadened to hare species (Lepus). The circulation of RHDV genotypes displays different virulences and a limited induction of cross-protective immunity. Interestingly, juvenile rabbits (<9 weeks of age) with an immature immune system display a general resistance to RHDV GI.1, and a limited resistance to RHDV GI.2 strains, whereas less than 3% of adult rabbits survive an infection by either RHDV GI.1. or GI.2. Several not-yet fully understood phenomena characterize the RHD. A very low infection dose followed by an extremely rapid viral replication could be simplified to the induction of a disseminated intravascular coagulopathy (DIC), a severe loss of lymphocytes—especially T-cells—and death within 36 to 72 h post infection. On the other hand, in animals surviving the infection or after vaccination, very high titers of RHDV-neutralizing antibodies were induced. Several studies have been conducted in order to deepen the knowledge about the virus’ genetics, epidemiology, RHDV-induced pathology, and the anti-RHDV immune responses of rabbits in order to understand the phenomenon of the juvenile resistance to this virus. Moreover, several approaches have been used to produce efficient vaccines in order to prevent an infection with RHDV. In this review, we discuss the current knowledge about anti-RHDV resistance and immunity, RHDV vaccination, and the further need to establish rationally-based RHDV vaccines.

scholarly journals Molecular evolution and structural analyses of the spike glycoprotein from Brazilian SARS-CoV-2 genomes: the impact of the fixation of selected mutations

2021 ◽  
Author(s):  
Patricia A. G. Ferrareze ◽  
Ricardo Zimerman ◽  
Vinicius Bonetti Franceschi ◽  
Gabriel Dickin Caldana ◽  
Paulo Netz ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Cell Receptor ◽  
Viral Fitness ◽  
Spike Protein ◽  
Energy Estimates ◽  
One Year ◽  
Multiple Amino Acid ◽  
The Impact

The COVID-19 pandemic caused by Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has reached by July 2021 almost 200 million cases and more than 4 million deaths worldwide since its beginning in late 2019, leading to enhanced concern in the scientific community and the general population. One of the most important pieces of this host-pathogen interaction is the spike protein, which binds to the human Angiotensin-converting enzyme 2 (hACE2) cell receptor, mediates the membrane fusion and is the major target of neutralizing antibodies against SARS-CoV-2. The multiple amino acid substitutions observed in this region, specially in the Receptor Binding Domain (RBD), mainly after almost one year of its emergence (late 2020), have enhanced the hACE2 binding affinity and led to several modifications in the mechanisms of SARS-CoV-2 pathogenesis, improving the viral fitness and/or promoting immune evasion, with potential impact in the vaccine development. In this way, the present work aimed to evaluate the effect of positively selected mutations fixed in the Brazilian SARS-CoV-2 lineages and to check for mutational evidence of coevolution. Additionally, we evaluated the impact of selected mutations identified in some of the VOC and VOI lineages (C.37, B.1.1.7, P.1, and P.2) of Brazilian samples on the structural stability of the spike protein, as well as their possible association with more aggressive infection profiles by estimating the binding affinity in the RBD-hACE2 complex. We identified 48 sites under selective pressure in Brazilian spike sequences, 17 of them with the strongest evidence by the HyPhy tests, including VOC related mutation sites 138, 142, 222, 262, 484, 681, and 845, among others. The coevolutionary analysis identified a number of 28 coevolving sites that were found not to be conditionally independent, such as the couple E484K - N501Y from P.1 and B.1.351 lineages. Finally, the molecular dynamics and free energy estimates showed the structural stabilizing effect and the higher impact of E484K for the improvement of the binding affinity between the spike RBD and the hACE2 in P.1 and P.2 lineages, as well as the stabilizing and destabilizing effects for the positively selected sites.

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