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Like other herpesviruses, it causes lifelong infection through the establishment of latency. Although reactivation from latency can cause significant morbidity and mortality in immunocompromised hosts, our understanding of HCMV latency and how it is maintained remains limited. Here, we discuss the characterized latency reservoir in hematopoietic cells in the bone marrow and the gaps in our knowledge of mechanisms that facilitate HCMV genome maintenance in dividing cells. We further review clinical evidence that strongly suggests the tissue origin of HCMV reactivation, and we outline similarities to murine cytomegalovirus where latency in tissue\u2010resident cells has been demonstrated. Overall, we think these observations call for a rethinking of HCMV latency reservoirs and point to potential sources of HCMV latency that reside in tissues.<\/jats:p>","DOI":"10.1111\/nyas.14994","type":"journal-article","created":{"date-parts":[[2023,4,7]],"date-time":"2023-04-07T11:14:55Z","timestamp":1680866095000},"page":"30-36","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["Rethinking human cytomegalovirus latency reservoir"],"prefix":"10.1111","volume":"1524","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5442-0201","authenticated-orcid":false,"given":"Michal","family":"Schwartz","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics Weizmann Institute of Science  Rehovot Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3583-5932","authenticated-orcid":false,"given":"Noam","family":"Stern\u2010Ginossar","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics Weizmann Institute of Science  Rehovot Israel"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2023,4,7]]},"reference":[{"key":"e_1_2_11_2_1","first-page":"1802","volume-title":"Fields virology","author":"Pellet P. 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