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By perturbing this balance, immunodeficiencies are expected to influence within-host viral evolution. Indeed, the presence of immunocompromised hosts has been argued to be a source of novel viral variants in some infectious diseases, including SARS-CoV-2. However, these arguments rest upon between-host models and so the role of immunodeficiencies on within-host evolution in primary infections is poorly understood. Using a mechanistic immunological model, here we consider how different immunodeficiencies shape the orchestration of the immune response during primary infection. We study how this alters the viral fitness landscape, thus speeding and slowing viral evolution. We show that during acute infections, while immunodeficiencies in neutrophils and interferon initially speed viral evolution, by the time the infection is cleared, mutations are at lower frequencies than in immunocompetent hosts. In persistent infections, we show that while T cell deficiencies slow viral evolution, interleukin-6 and macrophage deficiencies speed viral evolution. Finally, we show that positive epistatic interactions arising due to the immunological response will accelerate the evolution of viral mutations affecting the ability of virions to evade different aspects of the immune response and to enter host cells.<\/jats:p>","DOI":"10.1371\/journal.pcbi.1013967","type":"journal-article","created":{"date-parts":[[2026,2,25]],"date-time":"2026-02-25T18:35:32Z","timestamp":1772044532000},"page":"e1013967","update-policy":"https:\/\/doi.org\/10.1371\/journal.pcbi.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["Viral evolution during primary infection in immunocompromised hosts"],"prefix":"10.1371","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4852-4770","authenticated-orcid":true,"given":"Morgan","family":"Craig","sequence":"first","affiliation":[]},{"given":"Xiaoyan","family":"Deng","sequence":"additional","affiliation":[]},{"given":"David 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