Deciphering the Role of Sexual Transmission in Mpox Evolution

Mpox is a viral infectious disease caused by the monkeypox virus (MPXV), marked by a pox-like rash. Mpox recently gained significant attention during the 2022 global outbreak, when it showed sustained human-to-human transmission. Tied to this transmission pattern, a unique genomic signature (TC-to-TT) driven by human APOBEC3 activity was observed. This enzyme is abundantly expressed in immune-rich mucosal tissues, such as the anorectum and vaginal regions, which are also known to produce high MPXV viral loads. In 2023, a worrying outbreak of a new MPXV lineage, subclade Ib, was identified in Kamituga, Eastern Democratic Republic of Congo, and has been rapidly spreading across the country and internationally. This outbreak is strongly reminiscent of the global outbreak that was linked to sexual transmission, and exhibits the same APOBEC3 genomic signature. Therefore, in this proposal, we hypothesize that the introduction of this new lineage into sexual networks promotes mucosal transmission via immune-rich tissues, involving anorectal and vaginal mucosal tissues. APOBEC3 enzymatic activity in these tissues specifically might induce viral hypermutations, accelerating evolution and marking sexual transmission as a key driver of MPXV evolution. Proving this hypothesis would significantly impact our ability to steer outbreak mitigation efforts, such as targeted awareness, or vaccination campaigns to reach populations at higher risk.