Which SARS-CoV-2 spike mutants can evade T cell immunity?

Caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the coronavirus disease 2019 (COVID-19) pandemic continues to pose challenges to public health and economic well-being worldwide. To date, over 132.5 million cases of COVID-19 and over 2.8 million deaths have been confirmed.

A characteristic of this pandemic has been the emergence of numerous viral variants, some of which have spread rapidly to become the dominant strain. One such early variant was the D614G strain which then became the globally dominant lineage.

A new study, released on the bioRxiv* preprint server, reports the capability of a new variant of the virus to escape specific cellular immunity, while possessing a higher binding affinity to the host cell binding receptor, the angiotensin-converting enzyme 2 (ACE2).

Circulating variants

The D614G mutation markedly increased the viral binding affinity to the receptor, boosting infectivity and viral fitness, and thus enhancing its transmissibility. Much more recently, three variants of concern arose, termed the UK, South African and Brazil variants (B.1.1.7, also known as VOC 202012/01 or 20I/501Y.V1; B.1.351 (also known as 20H/501Y.V2); and P.1 (also known as 501Y.V3).

At the close of 2020, yet another variant has been circulating at a dominant level in California, USA, termed B.1.427/429 (also 111 known as CAL.20C). Cross-species transmission of the virus to mink was associated with the emergence of SARS-CoV-2 variant B.1.298.

Thus, genomic surveillance of circulating virus strains is essential to capture the effects of mutations on viral infectivity, virulence and immune resistance.

Unlike the UK variant, the B.1.351 and P.1 variants show moderate resistance to neutralization by antibodies specifically targeting the wildtype virus.

Cellular virus-specific immunity

The current study explores the resistance offered by new variants to HLA-restricted cellular immunity mediated by cytotoxic T lymphocytes (CTLs).

These cells recognize foreign antigenic sites, or epitopes, presented on host cells following viral infection via specific human leukocyte antigen (HLA) class I molecules, a phenomenon called HLA-restriction. Higher levels of virus-specific cellular immunity are correlated with less severe disease.

This may indicate the importance of HLA-restricted CTLs in regulating infection and illness with SARS-CoV-2.

The researchers observed two substitutions in the receptor-binding motif (RBM), L452R and Y453F, of the viral spike protein, to be associated with resistance to cellular immunity restricted by the HLA-I allele, HLA-A*24:02.

This allele is extensively found in many areas of the world, especially East and Southeast Asia.

Immunodominant RBM epitope

The investigators first showed that the nine-residue NF9 peptide is likely to be an immunodominant epitope presented by HLA A*24:02. This peptide is responsible for stimulating CD8+ CTLs in convalescent COVID-19 patients to proliferate to a tenfold higher number.

Conversely, these cells in seronegative individuals were present at low levels, and were not upregulated following exposure to NF9.

The CTLs in convalescent patients produced several cytokines when exposed to NF9, while surface CD107 expression indicates the cytotoxic nature of these cells.

The L452R is the most frequent mutant among the analyzed sequences in the RBM NF9 region, seen in over 5,600 sequences, while the Y453F substitution was seen in a smaller number, but still above 1,300 sequences.

These mutations are seen in the B.1.427/429 and B.1.1.298 lineages, respectively.

Lower antiviral response

When these spike mutants were individually tested for their ability to evade NF9-specific T cell immunity, the NF9-Y453F derivative showed significantly lower induction of gamma-interferons (IFN-γ), the primary antiviral cellular response, compared to wildtype NF9.

Interestingly, the NF9-L452R derivative failed to induce IFN-γ even at the highest concentration of 10 nM. In all five convalescent HLA-A*24 02 patient samples, this pattern was repeated, indicating these mutants evade cellular immunity mediated by this HLA antigen.

Increased ACE2 binding affinity

These mutations also conferred increased ACE2 binding affinity. While Y453F is on the binding interface of the viral RBM and the ACE2 receptor, like the N501 residue that is common to the three VOCs mentioned above, the L452 residue is not.

Nonetheless, all three were associated with higher affinity for human ACE2, and the L452R mutation also increased the surface expression of the spike protein, indicating a more stable protein.

Increased viral infectivity

Moreover, pseudovirus experiments with these spike mutants show that L452R substitution also enhances viral infectivity significantly, perhaps by causing a gain of complementary electrostatic interactions. This residue is located near the negatively charged patch of ACE2 residues, and the mutation may increase the intensity of electrostatic interaction.

Finally, the study demonstrates potentially increased viral replication with the L452R variant.

Spread of RBM mutants

The B.1.427/B.1.429 lineage harboring the L452R mutation was first detected in California at the end of September 2020, but has now become one of the dominant US lineages.

With the Y453F mutation, many sequences containing this variant were found in minks and cats infected with SARS-CoV-2 as well as in humans, indicating multiple transmissions between minks and humans, as well as humans and cats. The B.1.1.298 lineage containing the Y453F mutation formed only a proportion of this lineage.

This fraction was most prevalent from October to November 2020, but seems to have waned thereafter, not having been reported since January 18, 2021.

What are the implications?

Here we demonstrate that two recently emerging mutants in the receptor binding domain of the SARS-CoV-2 spike protein, L452R (in B.1.427/429) and Y453F (in B.1.298), can escape from the HLA-24-restricted cellular immunity. These mutations reinforce the affinity to viral receptor ACE2, and notably, the L452R mutation increases protein stability, viral infectivity, and potentially promotes viral replication.”

Functional cellular immunity has been thought to be key to modulating COVID-19 severity, and viral variants that allow evasion of HLA-restricted cellular immunity are concerning. In the current study, this is the more so as earlier research confirms that these variants are capable of escaping from both humoral and specific cellular immunity.

The broad host range adds to the potential of the virus for acquiring accumulated mutations that alter multiple viral functionalities, including pathogenicity, transmissibility, and infectivity.

The B.1.427/429 variant that harbors the L452R mutation has apparently emerged during the rapid spread of the virus among humans, improving viral fitness by its enhancing effect on viral replication.

Alternatively, the preponderance of the HLA-A24 in East Asian individuals, may have led to its emergence in California, which has the highest proportion of Asian Americans in the USA. For instance, in one town in this state with over 270,000 cases of COVID-19 at the time of the study, a fifth of all people had this HLA allele. This mutation may have allowed the virus to evade cytotoxic cellular immunity.

In many parts of Asia, despite the high prevalence of this allele, both the incidence and the mortality rate of COVID-19 are relatively low. Further studies will show whether these mutations also affect virulence and COVID-19 mortality.

*Important Notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.

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