SARS-CoV-2 escape from cytotoxic T cells during long-term COVID-19

Stanevich, Oksana V.; Alekseeva, Evgeniia; Sergeeva, Maria V.; Fadeev, Artem; Komissarova, Kseniya; Ivanova, Anna; Simakova, Tamara; Vasilyev, Kirill; Shurygina, Anna-Polina; Stukova, Marina; Safina, Ksenia R; Nabieva, Elena; Garushyants, Sofya K.; Klink, Galya V.; Bakin, Evgeny A.; Zabutova, Jullia V; Kholodnaya, A. N.; Lukina, O. V.; Skorokhod, Irina A; Ryabchikova, V. V.; Medvedeva, Nadezhda; Lioznov, Dmitry; Danilenko, Daria; Chudakov, Dmitriy M.; Komissarov, Andrey; Bazykin, Georgii A.

doi:10.1038/s41467-022-34033-x

Cited by 30 publications

(32 citation statements)

References 65 publications

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“…A study has found that a female patient diagnosed with immunodeficiency had continuous mutations of the virus in her body during infection, accumulating 40 mutations in total, which is far beyond the evolutionary rate of SARS‐CoV‐2 in the general population 23 . In this study, the mutations that occur in vitro without immune pressure are similar to the mutations that occur in the bodies of immunocompromised patients.…”

Section: Discussionmentioning

confidence: 56%

Are the original SARS‐CoV‐2 novel mutants from in vitro culture able to escape the immune response?

Mei

Peng

et al. 2023

Journal of Medical Virology

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Monitoring variations in the virus genome to understand the SARS-CoV-2 evolution and spread of the virus is extremely important. Seven early SARS-CoV-2 isolates in China were cultured in vitro and were analyzed for their viral infectivity through viral growth assay, tissue culture infectious dose (TCID 50 ) assay, spike protein quantification, and next generation sequencing analysis, and the resultant mutations in spike protein were used to generate the corresponding pseudoviruses for analysis of immune escape from vaccination and postinfection immunity. The results revealed that in vitro cultured SARS-CoV-2 virus had much higher mutation frequency (up to ~20 times) than that in infected patients, suggesting that SARS-CoV-2 diversify under favorable conditions. Monitoring viral mutations is not only helpful for better understanding of virus evolution and virulence change, but also the key to prevent virus transmission and disease progression. Compared with the D614G reference strain, a pseudovirus strain of SARS-CoV-2 was constructed with a high mutation rate site on the spike protein. We found some novel spike mutations during in vitro culture, such as E868Q, conferred further immune escape ability.

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Section: Discussionmentioning

confidence: 56%

Are the original SARS‐CoV‐2 novel mutants from in vitro culture able to escape the immune response?

Mei

Peng

et al. 2023

Journal of Medical Virology

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“…Our work, combined with Hamelin, Dolton’s and Swaminathan’s indicates that P→X mutations – which are now observed across Omicron variants that have infected large proportions of populations – in CD8+ T cell epitopes should be a priority for surveillance regarding T cell escape in HLA-B07 individuals and for associations with breakthrough infections. Overall, our data combined with recent studies are starting to indicate a more nuanced outlook regarding the impact of VOCs mutation on T cell responses, than the consensus [ 17 , 31 , 32 , 34 , 57 , 59 ].…”

Section: Discussionmentioning

confidence: 70%

“…However, not all HLA ligands can invoke T cell responses [ 38 , 39 ]. Furthermore, studies such as those of Naranbhai et al [ 17 ] and Reynolds et al [ 18 ] observed considerable numbers of patients with impaired T cell responses to Omicron infection [ 57 ]. Indeed, while widespread and complete escape is unlikely, it is plausible that detrimental mutations could impair certain individuals, e.g.…”

Section: Discussionmentioning

confidence: 99%

A systems approach evaluating the impact of SARS-CoV-2 variant of concern mutations on CD8+ T cell responses

Buckley

Lee

Antanaviciute

et al. 2023

Immunotherapy Advances

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T cell recognition of SARS-CoV-2 antigens after vaccination and/or natural infection has played a central role in resolving SARS-CoV-2 infections and generating adaptive immune memory. However, the clinical impact of SARS-CoV-2-specific T cell responses is variable and the mechanisms underlying T cell interaction with target antigens are not fully understood. This is especially true given the virus’ rapid evolution, which leads to new variants with immune escape capacity. In this study, we used the Omicron variant as a model organism and took a systems approach to evaluate the impact of mutations on CD8+ T cell immunogenicity. We computed an immunogenicity potential score for each SARS-CoV-2 peptide antigen from the ancestral strain and Omicron, capturing both antigen presentation and T cell recognition probabilities. By comparing ancestral vs. Omicron immunogenicity scores, we reveal a divergent and heterogeneous landscape of impact for CD8+ T cell recognition of mutated targets in Omicron variants. While T cell recognition of Omicron peptides is broadly preserved, we observed mutated peptides with deteriorated immunogenicity that may assist breakthrough infection in some individuals. We then combined our scoring scheme with an in-silico mutagenesis, to characterise the position- and residue-specific theoretical mutational impact on immunogenicity. While we predict many escape trajectories from the theoretical landscape of substitutions, our study suggests that Omicron mutations in T cell epitopes did not develop under cell-mediated pressure. Our study provides a generalisable platform for fostering a deeper understanding of existing and novel variant impact on antigen-specific vaccine- and/or infection-induced T cell immunity.

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“…Even in mild and moderate cases of COVID‐19, most recovered individuals linger with long COVID‐19 42 . In the case of immunocompromised patients, a recent study has shown that in long COVID‐19, SARS‐CoV‐2 is capable of escaping cytotoxic T cell‐mediated immunity, suggestive of the continuous and perilous evolution of the virus in humans 43 . Alarmingly, this pandemic has also significantly enhanced the burden of many fatal infectious diseases like HIV (human immune deficiency virus) and TB (tuberculosis) 44,45 .…”

Section: Introductionmentioning

confidence: 99%

“…42 In the case of immunocompromised patients, a recent study has shown that in long COVID-19, SARS-CoV-2 is capable of escaping cytotoxic T cell-mediated immunity, suggestive of the continuous and perilous evolution of the virus in humans. 43 Alarmingly, this pandemic has also significantly enhanced the burden of many fatal infectious diseases like HIV (human immune deficiency virus) and TB (tuberculosis). 44,45 Therefore, it is of paramount importance to understand the disease-causing mechanism of SARS-CoV-2 to efficiently manage the disease and devise combat strategies.…”

mentioning

confidence: 99%

Regulation of autophagy by SARS‐CoV‐2: The multifunctional contributions of ORF3a

Shariq

Malik

Sheikh

et al. 2023

Journal of Medical Virology

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Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) regulates autophagic flux by blocking the fusion of autophagosomes with lysosomes, causing the accumulation of membranous vesicles for replication. Multiple SARS-CoV-2 proteins regulate autophagy with significant roles attributed to ORF3a. Mechanistically, open reading frame 3a (ORF3a) forms a complex with UV radiation resistance associated, regulating the functions of the PIK3C3-1 and PIK3C3-2 lipid kinase complexes, thereby modulating autophagosome biogenesis. ORF3a sequesters VPS39 onto the late endosome/lysosome, inhibiting assembly of the soluble NSF attachement protein REceptor (SNARE) complex and preventing autolysosome formation. ORF3a promotes the interaction between BECN1 and HMGB1, inducing the assembly of PIK3CA kinases into the ER (endoplasmic reticulum) and activating reticulophagy, proinflammatory responses, and ER stress. ORF3a recruits BORCS6 and ARL8B to lysosomes, initiating the anterograde transport of the virus to the plasma membrane. ORF3a also activates the SNARE complex (STX4-SNAP23-VAMP7), inducing fusion of lysosomes with the plasma membrane for viral egress.These mechanistic details can provide multiple targets for inhibiting SARS-CoV-2 by developing host-or host-pathogen interface-based therapeutics.

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SARS-CoV-2 escape from cytotoxic T cells during long-term COVID-19

Cited by 30 publications

References 65 publications

Are the original SARS‐CoV‐2 novel mutants from in vitro culture able to escape the immune response?

Are the original SARS‐CoV‐2 novel mutants from in vitro culture able to escape the immune response?

A systems approach evaluating the impact of SARS-CoV-2 variant of concern mutations on CD8+ T cell responses

Regulation of autophagy by SARS‐CoV‐2: The multifunctional contributions of ORF3a

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