{"id":31737,"date":"2023-07-18T11:33:56","date_gmt":"2023-07-18T11:33:56","guid":{"rendered":"https:\/\/evaggelatos.com\/?p=31737"},"modified":"2023-07-18T11:33:56","modified_gmt":"2023-07-18T11:33:56","slug":"reverse-transcribed-sars-cov-2-rna-can-integrate-into-the-genome-of-cultured-human-cells-and-can-be-expressed-in-patient-derived-tissues","status":"publish","type":"post","link":"https:\/\/evaggelatos.com\/?p=31737","title":{"rendered":"Reverse-transcribed SARS-CoV-2 RNA can integrate into the genome of cultured human cells and can be expressed in patient-derived tissues"},"content":{"rendered":"<div class=\"article-citation\">\n<div class=\"article-source\">\n<div class=\"journal-actions dropdown-block\"><button id=\"full-view-journal-trigger\" class=\"journal-actions-trigger trigger\" tabindex=\"0\" title=\"Proceedings of the National Academy of Sciences of the United States of America\" aria-controls=\"full-view-journal\" aria-expanded=\"false\" aria-label=\"Toggle dropdown menu for journal Proceedings of the National Academy of Sciences of the United States of America\" data-pinger-ignore=\"\"> Proc Natl Acad Sci U S A <\/button><\/div>\n<\/div>\n<div><\/div>\n<div class=\"article-source\"><span class=\"cit\">2021 May 25;118(21):e2105968118.<\/span><\/div>\n<p><span class=\"citation-doi\"> doi: 10.1073\/pnas.2105968118. <\/span><\/div>\n<div class=\"inline-authors\">\n<div class=\"authors\">\n<div class=\"authors-list\"><span class=\"authors-list-item \"><a class=\"full-name\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Zhang+L&amp;cauthor_id=33958444\" data-ga-category=\"search\" data-ga-action=\"author_link\" data-ga-label=\"Liguo Zhang\">Liguo Zhang<\/a><sup class=\"affiliation-links\"><span class=\"author-sup-separator\">\u00a0<\/span><a class=\"affiliation-link\" title=\"Whitehead Institute for Biomedical Research, Cambridge, MA 02142.\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/33958444\/#full-view-affiliation-1\"> 1 <\/a><\/sup><span class=\"comma\">,\u00a0<\/span><\/span><span class=\"authors-list-item \"><a class=\"full-name\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Richards+A&amp;cauthor_id=33958444\" data-ga-category=\"search\" data-ga-action=\"author_link\" data-ga-label=\"Alexsia Richards\">Alexsia Richards<\/a><sup class=\"affiliation-links\"><span class=\"author-sup-separator\">\u00a0<\/span><a class=\"affiliation-link\" title=\"Whitehead Institute for Biomedical Research, Cambridge, MA 02142.\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/33958444\/#full-view-affiliation-1\"> 1 <\/a><\/sup><span class=\"comma\">,\u00a0<\/span><\/span><span class=\"authors-list-item \"><a class=\"full-name\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Barrasa+MI&amp;cauthor_id=33958444\" data-ga-category=\"search\" data-ga-action=\"author_link\" data-ga-label=\"M Inmaculada Barrasa\">M Inmaculada Barrasa<\/a><sup class=\"affiliation-links\"><span class=\"author-sup-separator\">\u00a0<\/span><a class=\"affiliation-link\" title=\"Whitehead Institute for Biomedical Research, Cambridge, MA 02142.\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/33958444\/#full-view-affiliation-1\"> 1 <\/a><\/sup><span class=\"comma\">,\u00a0<\/span><\/span><span class=\"authors-list-item \"><a class=\"full-name\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Hughes+SH&amp;cauthor_id=33958444\" data-ga-category=\"search\" data-ga-action=\"author_link\" data-ga-label=\"Stephen H Hughes\">Stephen H Hughes<\/a><sup class=\"affiliation-links\"><span class=\"author-sup-separator\">\u00a0<\/span><a class=\"affiliation-link\" title=\"HIV Dynamics and Replication Program, Center for Cancer Research, National Cancer Institute, Frederick, MD 21702.\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/33958444\/#full-view-affiliation-2\"> 2 <\/a><\/sup><span class=\"comma\">,\u00a0<\/span><\/span><span class=\"authors-list-item \"><a class=\"full-name\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Young+RA&amp;cauthor_id=33958444\" data-ga-category=\"search\" data-ga-action=\"author_link\" data-ga-label=\"Richard A Young\">Richard A Young<\/a><sup class=\"affiliation-links\"><span class=\"author-sup-separator\">\u00a0<\/span><a class=\"affiliation-link\" title=\"Whitehead Institute for Biomedical Research, Cambridge, MA 02142.\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/33958444\/#full-view-affiliation-1\"> 1 <\/a><span class=\"author-sup-separator\">\u00a0<\/span><a class=\"affiliation-link\" title=\"Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142.\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/33958444\/#full-view-affiliation-3\"> 3 <\/a><\/sup><span class=\"comma\">,\u00a0<\/span><\/span><span class=\"authors-list-item \"><a class=\"full-name\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/?term=Jaenisch+R&amp;cauthor_id=33958444\" data-ga-category=\"search\" data-ga-action=\"author_link\" data-ga-label=\"Rudolf Jaenisch\">Rudolf Jaenisch<\/a><sup class=\"affiliation-links\"><span class=\"author-sup-separator\">\u00a0<\/span><a class=\"affiliation-link\" title=\"Whitehead Institute for Biomedical Research, Cambridge, MA 02142; jaenisch@wi.mit.edu.\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/33958444\/#full-view-affiliation-4\"> 4 <\/a><span class=\"author-sup-separator\">\u00a0<\/span><a class=\"affiliation-link\" title=\"Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02142.\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/33958444\/#full-view-affiliation-3\"> 3 <\/a><\/sup><\/span><\/div>\n<\/div>\n<\/div>\n<div class=\"short-article-details\">Affiliations<\/div>\n<header id=\"heading\" class=\"heading\">\n<div id=\"full-view-heading\" class=\"full-view\">\n<ul id=\"full-view-identifiers\" class=\"identifiers\">\n<li><span class=\"identifier pubmed\"> <span class=\"id-label\"> PMID: <\/span> <strong class=\"current-id\" title=\"PubMed ID\">33958444<\/strong> <\/span><\/li>\n<li><span class=\"identifier pmc\"> <span class=\"id-label\"> PMCID: <\/span> <a class=\"id-link\" href=\"http:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/pmc8166107\/\" target=\"_blank\" rel=\"noopener\" data-ga-category=\"full_text\" data-ga-action=\"PMCID\"> PMC8166107 <\/a> <\/span><\/li>\n<li><span class=\"identifier doi\"> <span class=\"id-label\"> DOI: <\/span> <a class=\"id-link\" href=\"https:\/\/doi.org\/10.1073\/pnas.2105968118\" target=\"_blank\" rel=\"noopener\" data-ga-category=\"full_text\" data-ga-action=\"DOI\"> 10.1073\/pnas.2105968118 <\/a> <\/span><\/li>\n<\/ul>\n<p><span class=\"free-label\">Free PMC article<\/span><\/div>\n<\/header>\n<div id=\"abstract\" class=\"abstract\">\n<h2 class=\"title\">Abstract<\/h2>\n<div id=\"eng-abstract\" class=\"abstract-content selected\">\n<p>Prolonged detection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA and recurrence of PCR-positive tests have been widely reported in patients after recovery from COVID-19, but some of these patients do not appear to shed infectious virus. We investigated the possibility that SARS-CoV-2 RNAs can be reverse-transcribed and integrated into the DNA of human cells in culture and that transcription of the integrated sequences might account for some of the positive PCR tests seen in patients. In support of this hypothesis, we found that DNA copies of SARS-CoV-2 sequences can be integrated into the genome of infected human cells. We found target site duplications flanking the viral sequences and consensus LINE1 endonuclease recognition sequences at the integration sites, consistent with a LINE1 retrotransposon-mediated, target-primed reverse transcription and retroposition mechanism. We also found, in some patient-derived tissues, evidence suggesting that a large fraction of the viral sequences is transcribed from integrated DNA copies of viral sequences, generating viral-host chimeric transcripts. The integration and transcription of viral sequences may thus contribute to the detection of viral RNA by PCR in patients after infection and clinical recovery. Because we have detected only subgenomic sequences derived mainly from the 3&#8242; end of the viral genome integrated into the DNA of the host cell, infectious virus cannot be produced from the integrated subgenomic SARS-CoV-2 sequences.<\/p>\n<\/div>\n<p><strong class=\"sub-title\"> Keywords: <\/strong> LINE1; SARS-CoV-2; chimeric RNAs; genomic integration; reverse transcription.<\/p>\n<\/div>\n<p id=\"copyright\" class=\"copyright\">Copyright \u00a9 2021 the Author(s). Published by PNAS.<\/p>\n<div id=\"conflict-of-interest\" class=\"conflict-of-interest\">\n<h2 class=\"title\">Conflict of interest statement<\/h2>\n<div class=\"statement\">\n<p>Competing interest statement: R.J. is an advisor\/co-founder of Fate Therapeutics, Fulcrum Therapeutics, Omega Therapeutics, and Dewpoint Therapeutics. R.A.Y. is a founder and shareholder of Syros Pharmaceuticals, Camp4 Therapeutics, Omega Therapeutics, and Dewpoint Therapeutics.<\/p>\n<\/div>\n<\/div>\n<div id=\"figures\" class=\"figures\">\n<h2 class=\"title\">Figures<\/h2>\n<div id=\"slides-container\" class=\"figures-list\">\n<figure class=\"figure-item \" data-slide-index=\"0\" data-label-slug=\"fig-1\"><a class=\"figure-link\" role=\"button\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/instance\/8166107\/bin\/pnas.2105968118fig01.jpg\" aria-describedby=\"figure-caption-0\" data-image-width=\"788\" data-image-height=\"961\" data-image-alt=\"Fig. 1.\" data-pmc-id=\"PMC8166107\" data-figure-id=\"fig01\"> <img loading=\"lazy\" decoding=\"async\" id=\"article-image-0\" class=\"figure-thumb\" src=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/instance\/8166107\/bin\/pnas.2105968118fig01.gif\" alt=\"Fig. 1.\" width=\"173\" height=\"211\" \/> <\/a><\/p>\n<div class=\"figure-caption figure-caption-text\" aria-hidden=\"true\">\n<div class=\"caption-wrap\">\n<p>Fig. 1.<\/p>\n<div class=\"figure-caption-contents\">\n<p>SARS-CoV-2 RNA can be reverse\u2026<\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/figure>\n<figure class=\"figure-item \" data-slide-index=\"1\" data-label-slug=\"fig-2\"><a class=\"figure-link\" role=\"button\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/instance\/8166107\/bin\/pnas.2105968118fig02.jpg\" aria-describedby=\"figure-caption-1\" data-image-width=\"753\" data-image-height=\"955\" data-image-alt=\"Fig. 2.\" data-pmc-id=\"PMC8166107\" data-figure-id=\"fig02\"> <img loading=\"lazy\" decoding=\"async\" id=\"article-image-1\" class=\"figure-thumb\" src=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/instance\/8166107\/bin\/pnas.2105968118fig02.gif\" alt=\"Fig. 2.\" width=\"158\" height=\"201\" \/> <\/a><\/p>\n<div class=\"figure-caption figure-caption-text\" aria-hidden=\"true\">\n<div class=\"caption-wrap\">\n<p>Fig. 2.<\/p>\n<div class=\"figure-caption-contents\">\n<p>Evidence for integration of SARS-CoV-2\u2026<\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/figure>\n<figure class=\"figure-item \" data-slide-index=\"2\" data-label-slug=\"fig-3\"><a class=\"figure-link\" role=\"button\" href=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/instance\/8166107\/bin\/pnas.2105968118fig03.jpg\" aria-describedby=\"figure-caption-2\" data-image-width=\"762\" data-image-height=\"1010\" data-image-alt=\"Fig. 3.\" data-pmc-id=\"PMC8166107\" data-figure-id=\"fig03\"> <img loading=\"lazy\" decoding=\"async\" id=\"article-image-2\" class=\"figure-thumb\" src=\"https:\/\/www.ncbi.nlm.nih.gov\/pmc\/articles\/instance\/8166107\/bin\/pnas.2105968118fig03.gif\" alt=\"Fig. 3.\" width=\"191\" height=\"254\" \/> <\/a><\/p>\n<div class=\"figure-caption figure-caption-text\" aria-hidden=\"true\">\n<div class=\"caption-wrap\">\n<p>Fig. 3.<\/p>\n<div class=\"figure-caption-contents\">\n<p>Negative-strand viral RNA-seq reads suggest\u2026<\/p>\n<\/div>\n<\/div>\n<\/div>\n<\/figure>\n<\/div>\n<\/div>\n<div id=\"linked-commentary\" class=\"linked-articles\">\n<h2 class=\"title\">Comment in<\/h2>\n<ul class=\"item-list usa-unstyled-list\">\n<li class=\"full-docsum\">\n<div class=\"docsum-content\"><a class=\"docsum-title\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/34344759\/\" data-ga-category=\"comment_correction\" data-ga-action=\"34344759\" data-ga-label=\"linked-commentary\"> No evidence of SARS-CoV-2 reverse transcription and integration as the origin of chimeric transcripts in patient tissues. <\/a><\/p>\n<div class=\"docsum-citation full-citation\"><span class=\"docsum-authors full-authors\">Parry R, Gifford RJ, Lytras S, Ray SC, Coin LJM.<\/span> <span class=\"docsum-journal-citation full-journal-citation\">Proc Natl Acad Sci U S A. 2021 Aug 17;118(33):e2109066118. doi: 10.1073\/pnas.2109066118.<\/span> <span class=\"citation-part\">PMID: <span class=\"docsum-pmid\">34344759<\/span><\/span> <span class=\"free-resources spaced-citation-item citation-part\">Free PMC article.<\/span> <span class=\"no-abstract spaced-citation-item citation-part\">No abstract available.<\/span><\/div>\n<\/div>\n<\/li>\n<li class=\"full-docsum\">\n<div class=\"docsum-content\"><a class=\"docsum-title\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/34702741\/\" data-ga-category=\"comment_correction\" data-ga-action=\"34702741\" data-ga-label=\"linked-commentary\"> Assessment of potential SARS-CoV-2 virus integration into human genome reveals no significant impact on RT-qPCR COVID-19 testing. <\/a><\/p>\n<div class=\"docsum-citation full-citation\"><span class=\"docsum-authors full-authors\">Briggs E, Ward W, Rey S, Law D, Nelson K, Bois M, Ostrov N, Lee HH, Laurent JM, Mita P.<\/span> <span class=\"docsum-journal-citation full-journal-citation\">Proc Natl Acad Sci U S A. 2021 Nov 2;118(44):e2113065118. doi: 10.1073\/pnas.2113065118.<\/span> <span class=\"citation-part\">PMID: <span class=\"docsum-pmid\">34702741<\/span><\/span> <span class=\"free-resources spaced-citation-item citation-part\">Free PMC article.<\/span> <span class=\"no-abstract spaced-citation-item citation-part\">No abstract available.<\/span><\/div>\n<\/div>\n<\/li>\n<li class=\"full-docsum\">\n<div class=\"docsum-content\"><a class=\"docsum-title\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/34715873\/\" data-ga-category=\"comment_correction\" data-ga-action=\"34715873\" data-ga-label=\"linked-commentary\"> Integration of SARS-CoV-2 RNA in infected human cells by retrotransposons: an unlikely hypothesis and old viral relationships. <\/a><\/p>\n<div class=\"docsum-citation full-citation\"><span class=\"docsum-authors full-authors\">Grandi N, Tramontano E, Berkhout B.<\/span> <span class=\"docsum-journal-citation full-journal-citation\">Retrovirology. 2021 Oct 29;18(1):34. doi: 10.1186\/s12977-021-00578-w.<\/span> <span class=\"citation-part\">PMID: <span class=\"docsum-pmid\">34715873<\/span><\/span> <span class=\"free-resources spaced-citation-item citation-part\">Free PMC article.<\/span><\/div>\n<\/div>\n<\/li>\n<\/ul>\n<\/div>\n<div id=\"similar\" class=\"similar-articles\">\n<h2 class=\"title\">Similar articles<\/h2>\n<ul id=\"similar-articles-list\" class=\"articles-list\">\n<li class=\"full-docsum\">\n<div class=\"docsum-content\"><a class=\"docsum-title\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/36992338\/\" data-ga-category=\"similar_article\" data-ga-action=\"36992338\" data-ga-label=\"\"> LINE1-Mediated Reverse Transcription and Genomic Integration of SARS-CoV-2 mRNA Detected in Virus-Infected but Not in Viral mRNA-Transfected Cells. <\/a><\/p>\n<div class=\"docsum-citation full-citation\"><span class=\"docsum-authors full-authors\">Zhang L, Bisht P, Flamier A, Barrasa MI, Friesen M, Richards A, Hughes SH, Jaenisch R.<\/span> <span class=\"docsum-journal-citation full-journal-citation\">Viruses. 2023 Feb 25;15(3):629. doi: 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J. Med. 383, e120 (2020). &#8211; <a class=\"reference-link\" href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/32997903\/\" data-ga-category=\"reference\" data-ga-action=\"32997903\"> PubMed <\/a><\/li>\n<\/ol>\n<\/li>\n<\/ol>\n<div class=\"actions-bar\"><\/div>\n<\/div>\n<\/div>\n<\/div>\n","protected":false},"excerpt":{"rendered":"<p>Proc Natl Acad Sci U S A 2021 May 25;118(21):e2105968118. doi: 10.1073\/pnas.2105968118. Liguo Zhang\u00a0 1 ,\u00a0Alexsia Richards\u00a0 1 ,\u00a0M Inmaculada Barrasa\u00a0 1 ,\u00a0Stephen H Hughes\u00a0 2 ,\u00a0Richard A Young\u00a0 1 \u00a0 3 ,\u00a0Rudolf Jaenisch\u00a0 4 \u00a0 3 Affiliations PMID: 33958444 PMCID: PMC8166107 DOI: 10.1073\/pnas.2105968118 Free PMC article Abstract Prolonged detection of severe acute respiratory syndrome &hellip; <\/p>\n<p><a class=\"more-link btn\" href=\"https:\/\/evaggelatos.com\/?p=31737\">\u03a3\u03c5\u03bd\u03ad\u03c7\u03b5\u03b9\u03b1 \u03b1\u03bd\u03ac\u03b3\u03bd\u03c9\u03c3\u03b7\u03c2<\/a><\/p>\n","protected":false},"author":2,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"footnotes":""},"categories":[85],"tags":[],"class_list":["post-31737","post","type-post","status-publish","format-standard","hentry","category-85","item-wrap"],"_links":{"self":[{"href":"https:\/\/evaggelatos.com\/index.php?rest_route=\/wp\/v2\/posts\/31737","targetHints":{"allow":["GET"]}}],"collection":[{"href":"https:\/\/evaggelatos.com\/index.php?rest_route=\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/evaggelatos.com\/index.php?rest_route=\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/evaggelatos.com\/index.php?rest_route=\/wp\/v2\/users\/2"}],"replies":[{"embeddable":true,"href":"https:\/\/evaggelatos.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcomments&post=31737"}],"version-history":[{"count":1,"href":"https:\/\/evaggelatos.com\/index.php?rest_route=\/wp\/v2\/posts\/31737\/revisions"}],"predecessor-version":[{"id":31738,"href":"https:\/\/evaggelatos.com\/index.php?rest_route=\/wp\/v2\/posts\/31737\/revisions\/31738"}],"wp:attachment":[{"href":"https:\/\/evaggelatos.com\/index.php?rest_route=%2Fwp%2Fv2%2Fmedia&parent=31737"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/evaggelatos.com\/index.php?rest_route=%2Fwp%2Fv2%2Fcategories&post=31737"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/evaggelatos.com\/index.php?rest_route=%2Fwp%2Fv2%2Ftags&post=31737"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}