Seminal fluid enhances monkeypox virus infection via amyloidogenic fibrils

Mpox is a re-emerging zoonosis caused by monkeypox virus (MPXV), with recent outbreaks driven by sexual transmission. How semen contributes to MPXV infection, however, remains unclear. Here, we show that human seminal fluid potently enhances MPXV infection in susceptible target cells. Pre-exposure of MPXV to seminal fluid from multiple donors markedly increased infection of primary human fibroblasts and keratinocytes. Semen-derived peptide fragments that assemble into cationic amyloid fibrils (SEVI and SEM) enhanced infection of epithelial cells, primary monocytes, and ex vivo human skin, as well as clinical MPXV isolates and other orthopoxviruses. SEVI increased virion attachment and uptake, and fibril-targeting molecular tweezer (CLR01) disrupted seminal amyloids and abrogated enhancement. Notably, tecovirimat and brincidofovir retained activity under SEVI-enhanced conditions. These findings identify seminal amyloids as host factors that amplify MPXV infectivity and broaden cell tropism, suggesting that semen actively promotes sexual transmission of mpox.