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

Abstract

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.

Keywords: COVID-19 vaccines; SARS-CoV-2 genome; Spike protein; escape mutation; neutralizing antibodies (nAbs); receptor binding domain (RBD); variant of concern (VOC).

Figure 1

(A) SARS-CoV-2 structure of the SARS-CoV-2, comprising an ssRNA and 4 structural proteins interacts with the host cell through the ACE2 receptor (dark blue). Blue field represents inside the host cell, and yellow field outside the cell. (B) Changes in the spike during the virus-cell interaction. At the left, the inactive or ‘down’ conformation, reluctant to bind ACE2. Spike–ACE2 binding produces a conformational change in the S towards the ‘up’ configuration. This is followed by S1/S2 cleavage by host enzymes and activation of the entry to the cell. (C) Viral ssRNA enters the cell and produces pp1a and pp1ab, which will provide the RTC plus structural proteins (S, N, E, M) and accessory proteins (ORF). (D) N proteins are assembled with the new replicated viral ssRNA to form the vRNP. New viruses bud from the ERGIC and are released from the cell.

Figure 2

On the top, a schematic view of the SARS-CoV-2 genome that spans almost 30 kb. Polyprotein pp1a produces nsp1–nsp10 and pp1ab generates nsp1–nsp16. In the middle, the detailed structure of the spike protein. SS: signal sequence, NTD: N-terminal-domain, RBD: receptor binding domain, RBM: receptor binding motif, SD: subdomain, FP: fusion peptide, HR: heptad repeat, CH: central helix, CD: connector domain, TD: transmembrane domain, CT: cytoplasmic tail. Cleavage of the spike protein in SD1/SD2 yields spike subunits S1 and S2, activating the virus entry in the host cell. At the bottom, a schematic representation of the mutations included in the VOCs until September 2021. Red dotted lines point out mutations of concern that are shared by different variants.