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.