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The reason why some people have prolonged infection and how the virus persists for so long are still not fully understood. Recent studies suggested that the accumulation of intra-host single nucleotide variants (iSNVs) over the course of the infection might play an important role in persistence as well as emergence of mutations of concern. For this reason, we aimed to investigate the intra-host evolution of SARS-CoV-2 during prolonged infection. Thirty-three patients who remained reverse transcription polymerase chain reaction (RT-PCR) positive in the nasopharynx for on average 18\u2009days from the symptoms onset were included in this study. Whole-genome sequences were obtained for each patient at two different time points. Phylogenetic, populational, and computational analyses of viral sequences were consistent with prolonged infection without evidence of coinfection in our cohort. We observed an elevated within-host genomic diversity at the second time point samples positively correlated with cycle threshold (Ct) values (lower viral load). Direct transmission was also confirmed in a small cluster of healthcare professionals that shared the same workplace by the presence of common iSNVs. A differential accumulation of missense variants between the time points was detected targeting crucial structural and non-structural proteins such as Spike and helicase. Interestingly, longitudinal acquisition of iSNVs in Spike protein coincided in many cases with SARS-CoV-2 reactive and predicted T cell epitopes. We observed a distinguishing pattern of mutations over the course of the infection mainly driven by increasing A\u2192U and decreasing G\u2192A signatures. G\u2192A mutations may be associated with RNA-editing enzyme activities; therefore, the mutational profiles observed in our analysis were suggestive of innate immune mechanisms of the host cell defense. Therefore, we unveiled a dynamic and complex landscape of host and pathogen interaction during prolonged infection of SARS-CoV-2, suggesting that the host\u2019s innate immunity shapes the increase of intra-host diversity. Our findings may also shed light on possible mechanisms underlying the emergence and spread of new variants resistant to the host immune response as recently observed in COVID-19 pandemic.<\/jats:p>","DOI":"10.1093\/ve\/veab078","type":"journal-article","created":{"date-parts":[[2021,9,9]],"date-time":"2021-09-09T23:11:25Z","timestamp":1631229085000},"source":"Crossref","is-referenced-by-count":88,"title":["Intra-host evolution during SARS-CoV-2 prolonged infection"],"prefix":"10.1093","volume":"7","author":[{"given":"Carolina M","family":"Voloch","sequence":"first","affiliation":[{"name":"Departamento de Gen\u00e9tica, Instituto de Biologia, Universidade Federal do Rio de Janeiro , Av. Carlos Chagas Filho, 373 - Cidade Universit\u00e1ria da Universidade Federal do Rio de Janeiro - Ilha do Fund\u00e3o, Rio de Janeiro 21941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ronaldo","family":"da Silva Francisco Jr","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioinform\u00e1tica, Laborat\u00f3rio Nacional de Computa\u00e7\u00e3o Cient\u00edfica , Av. Get\u00falio Vargas, 333 - Quitandinha, Petr\u00f3polis 25651-076, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luiz G P","family":"de Almeida","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioinform\u00e1tica, Laborat\u00f3rio Nacional de Computa\u00e7\u00e3o Cient\u00edfica , Av. Get\u00falio Vargas, 333 - Quitandinha, Petr\u00f3polis 25651-076, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Otavio J","family":"Brustolini","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioinform\u00e1tica, Laborat\u00f3rio Nacional de Computa\u00e7\u00e3o Cient\u00edfica , Av. Get\u00falio Vargas, 333 - Quitandinha, Petr\u00f3polis 25651-076, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cynthia C","family":"Cardoso","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica, Instituto de Biologia, Universidade Federal do Rio de Janeiro , Av. Carlos Chagas Filho, 373 - Cidade Universit\u00e1ria da Universidade Federal do Rio de Janeiro - Ilha do Fund\u00e3o, Rio de Janeiro 21941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexandra L","family":"Gerber","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioinform\u00e1tica, Laborat\u00f3rio Nacional de Computa\u00e7\u00e3o Cient\u00edfica , Av. Get\u00falio Vargas, 333 - Quitandinha, Petr\u00f3polis 25651-076, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Paula de C","family":"Guimar\u00e3es","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioinform\u00e1tica, Laborat\u00f3rio Nacional de Computa\u00e7\u00e3o Cient\u00edfica , Av. Get\u00falio Vargas, 333 - Quitandinha, Petr\u00f3polis 25651-076, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabela de Carvalho","family":"Leit\u00e3o","sequence":"additional","affiliation":[{"name":"Instituto de Biof\u00edsica, Universidade Federal do Rio de Janeiro , Av. Carlos Chagas Filho, 373 - Cidade Universit\u00e1ria da Universidade Federal do Rio de Janeiro - Ilha do Fund\u00e3o, Rio de Janeiro 21941-170, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Diana","family":"Mariani","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica, Instituto de Biologia, Universidade Federal do Rio de Janeiro , Av. Carlos Chagas Filho, 373 - Cidade Universit\u00e1ria da Universidade Federal do Rio de Janeiro - Ilha do Fund\u00e3o, Rio de Janeiro 21941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor Akira","family":"Ota","sequence":"additional","affiliation":[{"name":"Departamento de Doen\u00e7as Infecciosas e Parasit\u00e1rias, Faculdade de Medicina, Universidade Federal do Rio de Janeiro , Av. Carlos Chagas Filho, 373, Edif\u00edcio do Centro de Ci\u00eancias da Sa\u00fade, Cidade Universit\u00e1ria da Universidade Federal do Rio de Janeiro - Ilha do Fund\u00e3o, Rio de Janeiro 21941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristiano X","family":"Lima","sequence":"additional","affiliation":[{"name":"Departamento de Cirurgia, Faculdade de Medicina, Universidade Federal de Minas Gerais , Av. Prof. Alfredo Balena, 190 - Santa Efig\u00eania, Belo Horizonte, MG 30130-100, Brazil"},{"name":"Simile Instituto de Imunologia Aplicada Ltda. R. S\u00e3o Paulo, 1932 , Belo Horizonte, 30170-132, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mauro M","family":"Teixeira","sequence":"additional","affiliation":[{"name":"Departamento de Bioquimica e Imunologia, Universidade Federal de Minas Gerais , Av. Ant\u00f4nio Carlos, 6627 - Pampulha, Belo Horizonte 31270-901, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Carolina F","family":"Dias","sequence":"additional","affiliation":[{"name":"Simile Instituto de Imunologia Aplicada Ltda. R. S\u00e3o Paulo, 1932 , Belo Horizonte, 30170-132, Brazil"},{"name":"Departamento de Bioquimica e Imunologia, Universidade Federal de Minas Gerais , Av. Ant\u00f4nio Carlos, 6627 - Pampulha, Belo Horizonte 31270-901, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rafael Mello","family":"Galliez","sequence":"additional","affiliation":[{"name":"Departamento de Doen\u00e7as Infecciosas e Parasit\u00e1rias, Faculdade de Medicina, Universidade Federal do Rio de Janeiro , Av. Carlos Chagas Filho, 373, Edif\u00edcio do Centro de Ci\u00eancias da Sa\u00fade, Cidade Universit\u00e1ria da Universidade Federal do Rio de Janeiro - Ilha do Fund\u00e3o, Rio de Janeiro 21941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D\u00e9bora Souza","family":"Faffe","sequence":"additional","affiliation":[{"name":"Instituto de Biof\u00edsica, Universidade Federal do Rio de Janeiro , Av. 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Carlos Chagas Filho, 373 - Cidade Universit\u00e1ria da Universidade Federal do Rio de Janeiro - Ilha do Fund\u00e3o, Rio de Janeiro 21941-902, Brazil"},{"name":"Departamento de Gen\u00e9tica, Ecologia e Evolu\u00e7\u00e3o, Instituto de Ci\u00eancias Biol\u00f3gicas, Universidade Federal de Minas Gerais , Av. Ant\u00f4nio Carlos, 6627, Belo Horizonte 31270-901, Brazil"},{"name":"Instituto D\u2019Or de Pesquisa e Ensino (IDOR) , Rua Diniz Cordeiro, 30, Rio de Janeiro 22281-100, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terezinha M P P","family":"Casti\u00f1eira","sequence":"additional","affiliation":[{"name":"Departamento de Doen\u00e7as Infecciosas e Parasit\u00e1rias, Faculdade de Medicina, Universidade Federal do Rio de Janeiro , Av. Carlos Chagas Filho, 373, Edif\u00edcio do Centro de Ci\u00eancias da Sa\u00fade, Cidade Universit\u00e1ria da Universidade Federal do Rio de Janeiro - Ilha do Fund\u00e3o, Rio de Janeiro 21941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Orlando C","family":"Ferreira","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica, Instituto de Biologia, Universidade Federal do Rio de Janeiro , Av. Carlos Chagas Filho, 373 - Cidade Universit\u00e1ria da Universidade Federal do Rio de Janeiro - Ilha do Fund\u00e3o, Rio de Janeiro 21941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amilcar","family":"Tanuri","sequence":"additional","affiliation":[{"name":"Departamento de Gen\u00e9tica, Instituto de Biologia, Universidade Federal do Rio de Janeiro , Av. Carlos Chagas Filho, 373 - Cidade Universit\u00e1ria da Universidade Federal do Rio de Janeiro - Ilha do Fund\u00e3o, Rio de Janeiro 21941-902, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Tereza","family":"R de Vasconcelos","sequence":"additional","affiliation":[{"name":"Laborat\u00f3rio de Bioinform\u00e1tica, Laborat\u00f3rio Nacional de Computa\u00e7\u00e3o Cient\u00edfica , Av. 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