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Enteroviruses represent a useful system to elucidate the details of this process. On the biochemical level, it is known that RNA recombination is catalyzed by the viral RNA-dependent RNA polymerase using a template-switching mechanism. For this mechanism to function in cells, the recombining genomes must be located in the same subcellular compartment. How a viral genome is trafficked to the site of genome replication and recombination, which is membrane associated and isolated from the cytoplasm, is not known. We hypothesized that genome translation was essential for colocalization of genomes for recombination. We show that complete inactivation of internal ribosome entry site (IRES)-mediated translation of a donor enteroviral genome enhanced recombination instead of impairing it. Recombination did not occur by a nonreplicative mechanism. Rather, sufficient translation of the nonstructural region of the genome occurred to support subsequent steps required for recombination. The noncanonical translation initiation factors, eIF2A and eIF2D, were required for IRES-independent translation. Our results support an eIF2A\/eIF2D-dependent mechanism under conditions in which the eIF2-dependent mechanism is inactive. Detection of an IRES-independent mechanism for translation of the enterovirus genome provides an explanation for a variety of debated observations, including nonreplicative recombination and persistence of enteroviral RNA lacking an IRES. The existence of an eIF2A\/eIF2D-dependent mechanism in enteroviruses predicts the existence of similar mechanisms in other viruses.<\/jats:p>","DOI":"10.1371\/journal.pbio.3001693","type":"journal-article","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T13:44:48Z","timestamp":1674481488000},"page":"e3001693","update-policy":"https:\/\/doi.org\/10.1371\/journal.pbio.corrections_policy","source":"Crossref","is-referenced-by-count":13,"title":["The enterovirus genome can be translated in an IRES-independent manner that requires the initiation factors eIF2A\/eIF2D"],"prefix":"10.1371","volume":"21","author":[{"given":"Hyejeong","family":"Kim","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Aponte-Diaz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohamad S.","family":"Sotoudegan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Djoshkun","family":"Shengjuler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jamie J.","family":"Arnold","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7564-5642","authenticated-orcid":true,"given":"Craig E.","family":"Cameron","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"340","published-online":{"date-parts":[[2023,1,23]]},"reference":[{"key":"pbio.3001693.ref001","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/0027-5107(64)90047-8","article-title":"The Relation of Recombination to Mutational Advance","volume":"106","author":"HJ Muller","year":"1964","journal-title":"Mutat Res"},{"issue":"2","key":"pbio.3001693.ref002","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1093\/genetics\/78.2.737","article-title":"The evolutionary advantage of recombination","volume":"78","author":"J. 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