Emerging variants of Mpox virus and tecovirimat resistance: Genomic insights and implications for treatment strategies

Abstract

Mpox is a zoonotic viral infection caused by the monkeypox virus (MPXV) genus Orthopoxvirus. The MPXV, possesses a large and complex double-stranded DNA genome, encoding approximately 190 genes. The virus has gained attention due to recent outbreaks and the emergence of resistant variants. MPXV exists in two distinct clades: Central African (Clade I) and West African (Clade II), with Clade I being more virulent. Genomic surveillance has revealed significant mutations across MPXV lineages, with Clade IIb, responsible for the 2022 outbreak, exhibiting rapid adaptation through APOBEC3-mediated deamination associated with sustained human-to-human transmission. The recent outbreak of highly mutated Clade 1b MPXV (hMpox-1) strain was associated with increased human-to-human transmission, underscoring the importance of monitoring viral mutations to track diversity and identify resistance to antiviral therapies. Tecovirimat, an antiviral drug authorized for treating Mpox, targets the F13L protein involved in viral egress. However, the rise of MPXV variants resistant to tecovirimat, linked to mutations in the F13L gene, presents a growing challenge. Mutations in the F13L gene, such as H238Q, A288P, A290V, D294V, P243S, N267D, A295E, I372N, and A184T, have been linked to resistance, reducing tecovirimat's efficacy. Therefore, understanding the Clade-specific mutation patterns and genomic adaptations offers crucial insights into the mechanisms driving resistant variant emergence to inform targeted therapeutic and vaccine development strategies, ensuring effective containment of future Mpox outbreaks. This review highlights the genomic diversity of MPXV, its implications for antiviral resistance, and strategies to enhance treatment effectiveness, particularly in vulnerable populations.