scholarly journals Spike Protein NTD mutation G142D in SARS-CoV-2 Delta VOC lineages is associated with frequent back mutations, increased viral loads, and immune evasion

2021 ◽  
Author(s):  
Lishuang Shen ◽  
Timothy J. Triche ◽  
Jennifer Dien Bard ◽  
Jaclyn A. Biegel ◽  
Alexander R. Judkins ◽  
...  
Keyword(s):  
Viral Load ◽  
Immune Evasion ◽  
Neutralizing Antibodies ◽  
Amino Acid Position ◽  
Spike Protein ◽  
Multiple Time ◽  
Viral Neutralization ◽  
Antibody Recognition ◽  
Recurrent Mutations ◽  
Multiple Time Points

AbstractThe significantly greater infectivity of the SARS-CoV-2 Delta variants of concern (VOC) is hypothesized to be driven by key mutations that result in increased transmissibility, viral load and/or evasion of host immune response. We surveyed the mutational profiles of Delta VOC genomes between September 2020 and mid-August 2021 and identified a previously unreported mutation pattern at amino acid position 142 in the N-terminal domain (NTD) of the spike protein which demonstrated multiple rounds of mutation from G142 to D142 and back. This pattern of frequent back mutations was observed at multiple time points and across Delta VOC sub-lineages. The etiology for these recurrent mutations is unclear but raises the possibility of host-directed editing of the SARS-CoV-2 genome. Within Delta VOC this mutation is associated with higher viral load, further enhanced in the presence of another NTD mutation (T95I) which was also frequently observed in these cases. Protein modeling of both mutations predicts alterations of the surface topography of the NTD by G142D, specifically disturbance of the ‘super site’ epitope that binds NTD-directed neutralizing antibodies (NAbs). The appearance of frequent and repeated G142D followed by D142G back mutations is previously unreported in SARS-CoV-2 and may represent viral adaptation to evolving host immunity characterized by increasing frequency of spike NAbs, from both prior infection and vaccine-based immunity. The emergence of alterations of the NTD in and around the main NAb epitope is a concerning development in the ongoing evolution of SARS-CoV-2 which may contribute to increased infectivity, immune evasion and ‘breakthrough infections’ characteristic of Delta VOC. Future vaccine and therapy development may benefit by recognizing the emergence of these novel spike NTD mutations and considering their impact on antibody recognition, viral neutralization, infectivity, replication, and viral load.

scholarly journals Persistent SARS-CoV-2 infection and intra-host evolution in association with advanced HIV infection

2021 ◽  
Author(s):  
Farina Karim ◽  
Mohamed YS Moosa ◽  
Bernadett Gosnell ◽  
Cele Sandile ◽  
Jennifer Giandhari ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Immune Evasion ◽  
Neutralizing Antibodies ◽  
Antiretroviral Treatment ◽  
Multiple Time ◽  
Whole Genome ◽  
Time Points ◽  
Multiple Time Points ◽  
Host Evolution ◽  
Antiretroviral Treatment Failure

While most people effectively clear SARS-CoV-2, there are several reports of prolonged infection in immunosuppressed individuals. Here we present a case of prolonged infection of greater than 6 months with the shedding of high titter SARS-CoV-2 in an individual with advanced HIV and antiretroviral treatment failure. Through whole-genome sequencing at multiple time points, we demonstrate the early emergence of the E484K substitution associated with escape from neutralizing antibodies, followed by other escape mutations and the N501Y substitution found in most variants of concern. This provides support to the hypothesis of intra-host evolution as one mechanism for the emergence of SARS-CoV-2 variants with immune evasion properties.

Mutation-induced Changes in the Receptor-binding Interface of the SARS-CoV-2 Delta Variant B.1.617.2 and Implications for Immune Evasion

2021 ◽  
Author(s):  
Prabin Baral ◽  
Nisha Bhattarai ◽  
Md Lokman Hossen ◽  
Vitalii Stebliankin ◽  
Bernard Gerstman ◽  
...  
Keyword(s):  
Receptor Binding ◽  
Immune Evasion ◽  
Genetic Variants ◽  
Neutralizing Antibodies ◽  
Structural Changes ◽  
Spike Protein ◽  
Sharp Rise ◽  
Stable Conformation ◽  
Binding Interface ◽  
Induced Changes

While the vaccination efforts against SARS-CoV-2 infections are ongoing worldwide, new genetic variants of the virus are emerging and spreading. Following the initial surges of the Alpha (B.1.1.7) and the Beta (B.1.351) variants, a more infectious Delta variant (B.1.617.2) is now surging, further deepening the health crises caused by the pandemic. The sharp rise in cases attributed to the Delta variant has made it especially disturbing and is a variant of concern. Fortunately, current vaccines offer protection against known variants of concern, including the Delta variant. However, the Delta variant has exhibited some ability to dodge the immune system as it is found that neutralizing antibodies from prior infections or vaccines are less receptive to binding with the Delta spike protein. Here, we investigated the structural changes caused by the mutations in the Delta variant's receptor-binding interface and explored the effects on binding with the ACE2 receptor as well as with neutralizing antibodies. We find that the receptor-binding beta-loop-beta motif adopts an altered but stable conformation causing separation in some of the antibody binding epitopes. Our study shows reduced binding of neutralizing antibodies and provides a possible mechanism for the immune evasion exhibited by the Delta variant.

scholarly journals Signatures in SARS-CoV-2 spike protein conferring escape to neutralizing antibodies

2021 ◽  
Vol 17 (8) ◽  
pp. e1009772
Author(s):  
Marta Alenquer ◽  
Filipe Ferreira ◽  
Diana Lousa ◽  
Mariana Valério ◽  
Mónica Medina-Lopes ◽  
...  
Keyword(s):  
Amino Acid ◽  
Immune Evasion ◽  
Neutralizing Antibodies ◽  
Immune Escape ◽  
Host Immunity ◽  
Arms Race ◽  
Spike Protein ◽  
Antibody Neutralization ◽  
Angiotensin Converting Enzyme 2 ◽  
The Core

Understanding SARS-CoV-2 evolution and host immunity is critical to control COVID-19 pandemics. At the core is an arms-race between SARS-CoV-2 antibody and angiotensin-converting enzyme 2 (ACE2) recognition, a function of the viral protein spike. Mutations in spike impacting antibody and/or ACE2 binding are appearing worldwide, imposing the need to monitor SARS-CoV2 evolution and dynamics in the population. Determining signatures in SARS-CoV-2 that render the virus resistant to neutralizing antibodies is critical. We engineered 25 spike-pseudotyped lentiviruses containing individual and combined mutations in the spike protein, including all defining mutations in the variants of concern, to identify the effect of single and synergic amino acid substitutions in promoting immune escape. We confirmed that E484K evades antibody neutralization elicited by infection or vaccination, a capacity augmented when complemented by K417N and N501Y mutations. In silico analysis provided an explanation for E484K immune evasion. E484 frequently engages in interactions with antibodies but not with ACE2. Importantly, we identified a novel amino acid of concern, S494, which shares a similar pattern. Using the already circulating mutation S494P, we found that it reduces antibody neutralization of convalescent and post-immunization sera, particularly when combined with E484K and with mutations able to increase binding to ACE2, such as N501Y. Our analysis of synergic mutations provides a signature for hotspots for immune evasion and for targets of therapies, vaccines and diagnostics.

scholarly journals Structural basis for antibody resistance to SARS-CoV-2 omicron variant

2021 ◽  
Author(s):  
Gabriele Cerutti ◽  
Yicheng Guo ◽  
Liu Lihong ◽  
Zhening Zhang ◽  
Liyuan Liu ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Receptor Binding ◽  
Neutralizing Antibodies ◽  
Spike Protein ◽  
Structural Basis ◽  
Receptor Binding Domain ◽  
Functional Studies ◽  
Antibody Recognition ◽  
Cryo Electron Microscopy ◽  
Antibody Resistance

The recently reported B.1.1.529 Omicron variant of SARS-CoV-2 includes 34 mutations in the spike protein relative to the Wuhan strain that initiated the COVID-19 pandemic, including 15 mutations in the receptor binding domain (RBD). Functional studies have shown omicron to substantially escape the activity of many SARS-CoV-2-neutralizing antibodies. Here we report a 3.1 Å resolution cryo-electron microscopy (cryo-EM) structure of the Omicron spike protein ectodomain. The structure depicts a spike that is exclusively in the 1-RBD-up conformation with increased mobility and inter-protomer asymmetry. Many mutations cause steric clashes and/or altered interactions at antibody binding surfaces, whereas others mediate changes of the spike structure in local regions to interfere with antibody recognition. Overall, the structure of the omicron spike reveals how mutations alter its conformation and explains its extraordinary ability to evade neutralizing antibodies.

scholarly journals Membrane fusion and immune evasion by the spike protein of SARS-CoV-2 Delta variant

2021 ◽  
Author(s):  
Jun Zhang ◽  
Tianshu Xiao ◽  
Yongfei Cai ◽  
Christy L. Lavine ◽  
Hanqin Peng ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Immune Evasion ◽  
Neutralizing Antibodies ◽  
Intervention Strategies ◽  
Spike Protein ◽  
Target Cells ◽  
Cellular Receptor ◽  
Receptor Binding Domain ◽  
Low Levels ◽  
Guide Intervention

AbstractThe Delta variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has outcompeted previously prevalent variants and become a dominant strain worldwide. We report here structure, function and antigenicity of its full-length spike (S) trimer in comparison with those of other variants, including Gamma, Kappa, and previously characterized Alpha and Beta. Delta S can fuse membranes more efficiently at low levels of cellular receptor ACE2 and its pseudotyped viruses infect target cells substantially faster than all other variants tested, possibly accounting for its heightened transmissibility. Mutations of each variant rearrange the antigenic surface of the N-terminal domain of the S protein in a unique way, but only cause local changes in the receptor-binding domain, consistent with greater resistance particular to neutralizing antibodies. These results advance our molecular understanding of distinct properties of these viruses and may guide intervention strategies.

scholarly journals Structure-guided evolution of antigenically distinct adeno-associated virus variants for immune evasion

2017 ◽  
Vol 114 (24) ◽  
pp. E4812-E4821 ◽  
Author(s):  
Longping Victor Tse ◽  
Kelli A. Klinc ◽  
Victoria J. Madigan ◽  
Ruth M. Castellanos Rivera ◽  
Lindsey F. Wells ◽  
...  
Keyword(s):  
Gene Therapy ◽  
Clinical Trials ◽  
Immune Evasion ◽  
Neutralizing Antibodies ◽  
Rhesus Macaques ◽  
Transduction Efficiency ◽  
Serum Samples ◽  
Antibody Recognition ◽  
Serotype 1 ◽  
High Degree

Preexisting neutralizing antibodies (NAbs) against adeno-associated viruses (AAVs) pose a major, unresolved challenge that restricts patient enrollment in gene therapy clinical trials using recombinant AAV vectors. Structural studies suggest that despite a high degree of sequence variability, antibody recognition sites or antigenic hotspots on AAVs and other related parvoviruses might be evolutionarily conserved. To test this hypothesis, we developed a structure-guided evolution approach that does not require selective pressure exerted by NAbs. This strategy yielded highly divergent antigenic footprints that do not exist in natural AAV isolates. Specifically, synthetic variants obtained by evolving murine antigenic epitopes on an AAV serotype 1 capsid template can evade NAbs without compromising titer, transduction efficiency, or tissue tropism. One lead AAV variant generated by combining multiple evolved antigenic sites effectively evades polyclonal anti-AAV1 neutralizing sera from immunized mice and rhesus macaques. Furthermore, this variant displays robust immune evasion in nonhuman primate and human serum samples at dilution factors as high as 1:5, currently mandated by several clinical trials. Our results provide evidence that antibody recognition of AAV capsids is conserved across species. This approach can be applied to any AAV strain to evade NAbs in prospective patients for human gene therapy.

scholarly journals Emergence in late 2020 of multiple lineages of SARS-CoV-2 Spike protein variants affecting amino acid position 677

2021 ◽  
Author(s):  
Emma B. Hodcroft ◽  
Daryl B. Domman ◽  
Daniel J. Snyder ◽  
Kasopefoluwa Y. Oguntuyo ◽  
Maarten Van Diest ◽  
...  
Keyword(s):  
New Mexico ◽  
Neutralizing Antibodies ◽  
Phylogenetic Analyses ◽  
Parallel Evolution ◽  
Protein S ◽  
Amino Acid Position ◽  
Proteolytic Processing ◽  
Cell Entry ◽  
Spike Protein ◽  
South Central

AbstractThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein (S) plays critical roles in host cell entry. Non-synonymous substitutions affecting S are not uncommon and have become fixed in a number of SARS-CoV-2 lineages. A subset of such mutations enable escape from neutralizing antibodies or are thought to enhance transmission through mechanisms such as increased affinity for the cell entry receptor, angiotensin-converting enzyme 2 (ACE2). Independent genomic surveillance programs based in New Mexico and Louisiana contemporaneously detected the rapid rise of numerous clade 20G (lineage B.1.2) infections carrying a Q677P substitution in S. The variant was first detected in the US on October 23, yet between 01 Dec 2020 and 19 Jan 2021 it rose to represent 27.8% and 11.3% of all SARS-CoV-2 genomes sequenced from Louisiana and New Mexico, respectively. Q677P cases have been detected predominantly in the south central and southwest United States; as of 03 Feb 2021, GISAID data show 499 viral sequences of this variant from the USA. Phylogenetic analyses revealed the independent evolution and spread of at least six distinct Q677H sub-lineages, with first collection dates ranging from mid-August to late November 2020. Four 677H clades from clade 20G (B.1.2), 20A (B.1.234), and 20B (B.1.1.220, and B.1.1.222) each contain roughly 100 or fewer sequenced cases, while a distinct pair of clade 20G clusters are represented by 754 and 298 cases, respectively. Although sampling bias and founder effects may have contributed to the rise of S:677 polymorphic variants, the proximity of this position to the polybasic cleavage site at the S1/S2 boundary are consistent with its potential functional relevance during cell entry, suggesting parallel evolution of a trait that may confer an advantage in spread or transmission. Taken together, our findings demonstrate simultaneous convergent evolution, thus providing an impetus to further evaluate S:677 polymorphisms for effects on proteolytic processing, cell tropism, and transmissibility.

scholarly journals Physical activity levels among ovarian cancer survivors: a prospective longitudinal cohort study

2021 ◽  
pp. ijgc-2020-002107
Author(s):  
Tamara Jones ◽  
Carolina Sandler ◽  
Dimitrios Vagenas ◽  
Monika Janda ◽  
Andreas Obermair ◽  
...  
Keyword(s):  
Physical Activity ◽  
Ovarian Cancer ◽  
Stage Iv ◽  
Multiple Time ◽  
Activity Levels ◽  
Prospective Longitudinal Study ◽  
Physical Activity Advice ◽  
Physical Activity Levels ◽  
Multiple Time Points ◽  
Prospective Longitudinal

ObjectivePhysical activity following cancer diagnosis is associated with improved outcomes, including potential survival benefits, yet physical activity levels among common cancer types tend to decrease following diagnosis and remain low. Physical activity levels following diagnosis of less common cancers, such as ovarian cancer, are less known. The objectives of this study were to describe physical activity levels and to explore characteristics associated with physical activity levels in women with ovarian cancer from pre-diagnosis to 2 years post-diagnosis.MethodsAs part of a prospective longitudinal study, physical activity levels of women with ovarian cancer were assessed at multiple time points between pre-diagnosis and 2 years post-diagnosis. Physical activity levels and change in physical activity were described using metabolic equivalent task hours and minutes per week, and categorically (sedentary, insufficiently, or sufficiently active). Generalized Estimating Equations were used to explore whether participant characteristics were related to physical activity levels.ResultsA total of 110 women with ovarian cancer with a median age of 62 years (range 33–88) at diagnosis were included. 53–57% of the women were sufficiently active post-diagnosis, although average physical activity levels for the cohort were below recommended levels throughout the 2-year follow-up period (120–142.5min/week). A decrease or no change in post-diagnosis physical activity was reported by 44–60% of women compared with pre-diagnosis physical activity levels. Women diagnosed with stage IV disease, those earning a lower income, those receiving chemotherapy, and those currently smoking or working were more likely to report lower physical activity levels and had increased odds of being insufficiently active or sedentary.ConclusionsInterventions providing patients with appropriate physical activity advice and support for behavior change could potentially improve physical activity levels and health outcomes.

scholarly journals The molecular make up of smoldering myeloma highlights the evolutionary pathways leading to multiple myeloma

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Eileen M. Boyle ◽  
Shayu Deshpande ◽  
Ruslana Tytarenko ◽  
Cody Ashby ◽  
Yan Wang ◽  
...  
Keyword(s):  
Tumour Suppressor Genes ◽  
Multiple Time ◽  
Clonal Structure ◽  
Time To Progression ◽  
Novel Mutations ◽  
Evolutionary Patterns ◽  
Risk Of Progression ◽  
Multiple Time Points ◽  
Smoldering Myeloma ◽  
Copy Number Changes

AbstractSmoldering myeloma (SMM) is associated with a high-risk of progression to myeloma (MM). We report the results of a study of 82 patients with both targeted sequencing that included a capture of the immunoglobulin and MYC regions. By comparing these results to newly diagnosed myeloma (MM) we show fewer NRAS and FAM46C mutations together with fewer adverse translocations, del(1p), del(14q), del(16q), and del(17p) in SMM consistent with their role as drivers of the transition to MM. KRAS mutations are associated with a shorter time to progression (HR 3.5 (1.5–8.1), p = 0.001). In an analysis of change in clonal structure over time we studied 53 samples from nine patients at multiple time points. Branching evolutionary patterns, novel mutations, biallelic hits in crucial tumour suppressor genes, and segmental copy number changes are key mechanisms underlying the transition to MM, which can precede progression and be used to guide early intervention strategies.

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