Orthopoxvirus is a genus of viruses in the family Poxviridae and subfamily Chordopoxvirinae. Vertebrates, including mammals and humans, and arthropods serve as natural hosts. Currently, 10 species are in this genus, including the type species Vaccinia virus. Diseases associated with this genus include smallpox, cowpox, horsepox, and monkeypox. The most infamous member of the genus is Variola virus, which causes smallpox. It was eradicated using Vaccinia virus as a vaccine. Group: dsDNA Among the path of evolution of the Orthopoxvirus species, many genes are truncated (but still functional), fragmented, or lost. Cowpox strains tend to have most intact genes. Predicting the phylogeny by sequence or by gene content produces somewhat different results: Some of the differences in the two trees are attributed to the procedure of passage in producing vaccinia strains. The MVA (Ankara) strain in this regard has a lot of gene loss related to in vitro passage, and horsepox being a vaccinia strain found in a natural outbreak has less. The orthopoxviruses are enveloped with brick-shaped geometries and virion dimensions around 200 nm wide and 250 nm long. Orthopoxvirus genomes are linear and around 170–250 kb in length. Viral replication is cytoplasmic. Entry into the host cell is achieved by attachment of the viral proteins to host glycosaminoglycans (GAGs), which mediate cellular endocytosis of the virus. Fusion of the viral envelope with the plasma membrane releases the viral core into the host cytoplasm. Expression of early-phase genes by viral RNA polymerase begins at 30 minutes after infection. The viral core is completely uncoated as early expression ends, releasing the viral genome into the cytoplasm. At this point, intermediate genes are expressed, triggering genomic DNA replication by the viral DNA polymerase about 100 minutes post-infection. Replication follows the DNA strand displacement model. Late genes are expressed from 140 min to 48 hours postinfection, producing all viral structural proteins. Assembly of progeny virions begins in cytoplasmic viral factories, producing an spherical immature particle. This virus particle matures into the brick-shaped intracellular mature virion, which can be released upon cell lysis, or can acquire a second membrane from the Golgi apparatus and bud as extracellular enveloped virions. In this latter case, the virion is transported to the plasma membrane via microtubules. Some orthopoxviruses, including the monkeypox, cowpox, and buffalopox viruses, have the ability to infect non-reservoir species. Others, such as ectromelia and camelpox viruses, are highly host-specific. Vaccinia virus, maintained in vaccine institutes and research laboratories, has a very wide host range. Vaccine-derived vaccinia has been found replicating in the wild in Brazil, where it has caused infections in rodents, cattle, and even humans. Following the eradication of variola virus, camelpox has become one of the most economically important Orthopoxvirus infections due to the dependence of many subsistence-level nomadic communities on camels.