4. Mpox Genetic Clades and Evolution
Experts in Mpox virology, evolutionary biology, and councils of research
institutes from around the world reviewed the phylogeny and nomenclature
of known and unknown Mpox virus variations or clades. They discussed the
characteristics and evolution of several Mpox virus strains, differences
in their apparent phylogenetic and clinical makeup, and any potential
repercussions for virologic and evolutionary research as well as public
health in the future. 24,25.
The panel decided on new nomenclature for the virus clades that adheres
to professional norms. They agreed on the listing and categorization of
virus clades for genomic sequence repository websites. Experts in
virology, evolutionary biology, and councils of research institutes from
around the world reviewed the phylogeny and nomenclature of known and
unknown Mpox virus variations or clades. They discussed the
characteristics and evolution of several Mpox virus strains, differences
in their apparent phylogenetic and clinical composition, and any
potential repercussions for virological and evolutionary research as
well as public health in the future. The panel decided on new
nomenclature for the virus clades that adheres to professional norms.
They reached an agreement on the listing and categorization of virus
clades on genomic sequence repository sites26.
In the proper naming system, the clade will be denoted by a Roman
number, and the subclades will be denoted by a lower-case alphanumeric
character. Hence, Clade I, Clade IIa, and Clade IIb are included in the
revised terminology, with Clade IIb denoting the collection of variants
that were primarily in use during the global outbreakof 202227. Lineages will be given the names that the experts
have suggested as the outbreak progresses. If further time is required,
the experts will convene. The new names for the clades should go into
force immediately away, while work on the names of the diseases and
viruses continues28,29. Different strains of Monkeypox
virus (MPXV) exhibit genetic polymorphism and genomic instability,
contributing to strain evolution. MPXV is a DNA virus that undergoes
frequent mutations, enabling rapid spread. The emergence of well-adapted
variants can have devastating global consequences. Minor genetic changes
facilitate host adaptation, with moderate transmission rates being more
common. Genetic mutations, both stabilizing and destabilizing, enhance
viral fitness and support interhuman transmission. Different strains of
Monkeypox virus (MPXV) exhibit variations in their genome sizes, ranging
from 190,083 to 206,372 base pairs. These strains are classified into
two clades: West African and Congo Basin. Through epidemiological
studies, researchers have observed differences in the severity of MPX
infection in various regions. By comparing three West African strains
(SL-V70, complement control protein [COP]-58, and WRAIR-61) with a
Central African strain (ZAI-96), it was found that there is a nucleotide
variance of approximately 0.55% to 0.56%. The primary distinctions
between these strains lie in the orthologs of the BR-203C, BR-209, and
COP-C3L genes. The BR-203 gene, for instance, encodes a complete protein
comprising 221 amino acids. Curiously, the West African strain of
Monkeypox virus (MPXV) encodes only a partial N-terminal fragment,
consisting of approximately 51 amino acids, for the specific gene under
investigation. Intriguingly, this gene is an ortholog of the M-T4 gene
that exists in the myxoma virus. The myxoma virus is notorious for
causing myxomatosis, a disease affecting European rabbits. Intriguingly,
scientific studies have shown that deleting the M-T4 gene results in a
heightened inflammatory response. This finding suggests that this gene
regulates the immune response to viral infections.
BR-209 acts as an IL-1β binding protein, preventing the binding of IL-1β
to the IL-1 receptor. The cytokine IL-1, present in forms of IL-1α,
IL-1β, and IL-1 receptor antagonist, affects the inflammatory response.
One of these mechanisms involves the production of vIL-1βBP. By binding
to IL-1β, vIL-1βBP prevents IL-1β from interacting with its cellular
receptors, inhibiting its signaling and dampening the immune response.
The COP-C3L gene in vaccinia virus codes for a secreted protein called
vaccinia virus COP (VCP). The Central African strain of MPXV expresses a
shorter protein known as MPX inhibitor of complement enzymes (MOPICE),
which is the ortholog of COP-C3L gene. The variola virus, responsible
for smallpox, contains the ortholog known as smallpox inhibitor of
complement enzymes (SPICE). MPXV strains exhibit genetic diversity, with
the Congo Basin clades being more severe and associated with human
infections worldwide. Understanding the roles of these genes in MPXV
pathogenesis is essential for comprehending the complex interactions and
their contributions to the virus’s disease-causing mechanisms.
The 2022 outbreak of MPXV is associated with a divergent branch,
referred to as lineage B.1, which is derived from lineage A.1. Lineage
A.1 has been associated with MPXV exports from Nigeria to the United
Kingdom, Israel, and Singapore in 2018-2019. The 2022 MPXV outbreak may
be attributed to the ongoing spread and evolution of the virus from the
2017-2018 Nigeria outbreak. Poxviruses, including MPXV, have a lower
mutation rate compared to RNA viruses. However, the 2022 MPXV shows a
rapid divergence from the 2018 virus, suggesting rapid adaptation to its
host. APOBEC3 editing contributes to the mutation rate, with 90% of new
nucleotide changes due to this process. Recombination plays a crucial
role in poxvirus evolution, with the first natural recombination event
in MPXV. Gene loss and amplification are important factors in MPXV’s
evolution, with the West African clade having larger genomes and more
gene content. Monitoring non-synonymous mutations, genome ends, and gene
content is crucial for understanding the evolutionary dynamics and
possible adaptations of MPXV. The monkeypox virus’s development and
transmission are influenced by point mutations in several proteins,
leading to the multi-country outbreak in 2022. The virus originated from
the MPXV/United States/2021/MD virus and has evolved through ten common
amino acid alterations. The B.1 viruses, which were transferred from
Nigeria between 2018 and 2019, have specific amino acid changes in 22 of
the 26 proteins. The study also examined characteristics of codon use
and host adaptability, revealing a bias in codon use in genes undergoing
nucleotide alterations in the B.1 lineage. Selection pressure, rather
than mutation pressure, played a significant role in the evolution of
genes expressing nucleotide mutations in the B.1 lineage. Monitoring and
analyzing the virus’s genetic alterations is crucial for improving our
understanding of its behavior and guiding effective preventative and
control efforts.