Poxvirus Host-Range Determinants: SAMD9/9L and Beyond.

The recent global spread of mpox virus, facilitated by a newly established human-to-human transmission mode, has rekindled interest in poxviruses and the molecular factors defining their host range. Poxviruses employ host-range factors, a subset of their immune evasion proteins, to overcome cell-intrinsic defenses in specific cell types or host species. Over the past decade, investigations of these factors have revealed previously unrecognized antiviral mechanisms and expanded our understanding of innate immunity. Among the key developments are the discovery of novel restriction factors, including SAMD9 and SAMD9L (SAMD9/9L), and expanded roles for established antiviral proteins such as IFITs, FAM111A, and ZAP. These advances not only clarify how poxvirus host range is determined but also offer valuable insights into the complexity and evolution of mammalian innate immunity. Here, I highlight new findings on poxvirus host-range determinants, with a particular focus on SAMD9/9L and the three distinct classes of poxvirus host-range factors that antagonize them.