「ウイルスは長期的には病原性を低下させるように進化する」というよくある従来の言説は誤りである

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◆The evolution of SARS-CoV-2【nature reviews microbiology　2023年4月5日】

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused millions of deaths and substantial morbidity worldwide. Intense scientific effort to understand the biology of SARS-CoV-2 has resulted in daunting numbers of genomic sequences. We witnessed evolutionary events that could mostly be inferred indirectly before, such as the emergence of variants with distinct phenotypes, for example transmissibility, severity and immune evasion. This Review explores the mechanisms that generate genetic variation in SARS-CoV-2, underlying the within-host and population-level processes that underpin these events. We examine the selective forces that likely drove the evolution of higher transmissibility and, in some cases, higher severity during the first year of the pandemic and the role of antigenic evolution during the second and third years, together with the implications of immune escape and reinfections, and the increasing evidence for and potential relevance of recombination. In order to understand how major lineages, such as variants of concern (VOCs), are generated, we contrast the evidence for the chronic infection model underlying the emergence of VOCs with the possibility of an animal reservoir playing a role in SARS-CoV-2 evolution, and conclude that the former is more likely. We evaluate uncertainties and outline scenarios for the possible future evolutionary trajectories of SARS-CoV-2.

Introduction

The COVID-19 pandemic is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a betacoronavirus, which is closely related to the human SARS-CoV virus — the cause of the 2002–2004 SARS outbreak. Three years since the start of the first coronavirus pandemic in living memory, attention understandably turns to what a future with the SARS-CoV-2 virus might look like. The pandemic also saw the generation of unparalleled amounts of genomic data for a single pathogen, serving to combat but also understand the biology of this virus. We witnessed evolutionary events that have previously been largely the preserve of indirect inference, including the diversification of SARS-CoV-2 into variants with distinct phenotypic characteristics including transmissibility, severity and immune evasion. Tracking the evolution of this pathogen in real time offers hope of understanding the processes generating this diversity, potentially predicting possible future evolutionary trajectories of the virus, and offering avenues for prevention and treatment. To facilitate such possibilities there is a pressing need to critically review the key drivers of SARS-CoV-2 evolution, and to explain the processes that generate diversity and novelty in the virus.

Like most RNA viruses, coronaviruses evolve rapidly, their evolution occurring on timescales of months or years and often observable and measurable. Evolution occurs on comparable timescales with the virus’ transmission events and ecological dynamics (such as changes in the number of infectious individuals over time, immunity profiles and human mobility). As a consequence, evolutionary, ecological and epidemiological processes impact each other, a feature of RNA viruses. Evolution in viruses is driven by the rate at which mutations are generated and spread through populations. Natural selection will act to fix advantageous mutations, such as, for example, the D614G mutation, which confers elevated transmissibility. Viral evolution involves an additional level of complexity, as viruses replicate and evolve within individuals, but they must also successfully transmit person to person, resulting in evolution at a different scale. Most variation is lost during the tight bottlenecks imposed at transmission, whereas some mutations are often passed on by chance, without selective advantage. In addition to these population-level processes, as viral lineages diversify, including into potentially antigenically distinct strains, higher-level processes such as lineage competition and extinction emerge.

In this Review, we consider the evolution of SARS-CoV-2 at different scales, the phases of the COVID-19 pandemic, factors that drive the evolution of the virus, theories for the emergence of epidemiologically important variants and potential future evolutionary scenarios and their likely public health repercussions.

The generation of diversity during the SARS-CoV-2 pandemic

Mutation rate: replication fidelity and host-mediated genome editing

A key determinant of the rate at which a virus evolves is its mutation rate. This is the intrinsic rate at which genetic changes emerge per replication cycle, a biochemical property determined by the replication fidelity of a virus’ polymerase enzyme. These genetic changes are the ‘raw material’ on which selection acts. Most mutations are deleterious, and virions hosting them fail to replicate. SARS-CoV-2 mutation rate estimates of around 1 × 10–6–2 × 10–6 mutations per nucleotide per replication cycle are consistent with previous estimates in other betacoronaviruses. These mutation rates lie below the range of rates that are typical for other RNA viruses such as hepatitis C virus (HCV; ~10–5 × 10–6 mutations per nucleotide per replication cycle) and human immunodeficiency virus (HIV; ~10–4  × 10–6 mutations per nucleotide per replication cycle), which, unlike coronaviruses, lack a 3′ exonuclease proofreading mechanism in their replication machinery. Insertions and deletions result from replication errors and can also generate diversity, such as the deletion at position 69–70 of the spike gene responsible for the S-gene drop-out that was instrumental in detecting the SARS-CoV-2 Alpha variant, and has been reported to be associated with increased infectivity.

In addition to RNA replication errors, host-mediated genome editing by innate cell defence mechanisms may introduce substantial numbers of directed mutations into the SARS-CoV-2 genome, and thus may influence its evolutionary rate. Cellular mutational drivers include members of the apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC) family, including APOBEC1, APOBEC3A and APOBEC3G that demonstrate editing activity for numerous DNA and RNA virus and retroviral genomes, including SARS-CoV-2 (ref.). APOBEC activity has been inferred bioinformatically through observations of a substantial excess of C → U transitions over all other mutations. SARS-CoV-2 genomes may also be edited by different cellular antiviral proteins (adenosine deaminases that act on RNA 1 (ADAR1)), leading to A → G mutations (and U → C mutations in opposite genomic strands).

The potential editing-associated C → U mutations in the SARS-CoV-2 genome sequences introduce complexities to SARS-CoV-2 evolutionary genomic analysis. C → U mutations account, in part, for the strikingly high ratio of non-synonymous changes in SARS-CoV-2 genomes compared with those at synonymous sites; the mean dN/dS ratio is ~0.7–0.8, which is a measure of the ratio of non-synonymous mutations per non-synonymous site (dN) to synonymous mutations per synonymous site (dS). Such mutations may be a potent driver of antigenic or phenotypic changes. Furthermore, C → U mutations may be skewed towards mutational ‘hot spots’ generated by RNA structures and specific base contexts. Repeated cycles of C → U transitions and selective reversions may create a large number of homoplasic sites20,23,24 and, therefore, convergence in otherwise genetically divergent strains.