{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T02:14:26Z","timestamp":1789352066798,"version":"build-2803163510"},"reference-count":33,"publisher":"American Society for Microbiology","issue":"24","license":[{"start":{"date-parts":[[2014,12,15]],"date-time":"2014-12-15T00:00:00Z","timestamp":1418601600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/journals.asm.org\/non-commercial-tdm-license"}],"content-domain":{"domain":["journals.asm.org"],"crossmark-restriction":true},"short-container-title":["J Virol"],"published-print":{"date-parts":[[2014,12,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n          <jats:p>\n            The helper-dependent adeno-associated virus type 2 (AAV-2) exhibits complex interactions with its helper adenovirus. Whereas AAV-2 is dependent on adenoviral functions for productive replication, it conversely inhibits adenoviral replication, both when its genome is present in\n            <jats:italic>trans<\/jats:italic>\n            after coinfection with both viruses and when it is present in\n            <jats:italic>cis<\/jats:italic>\n            , as in the production of recombinant adenovirus (rAd)\/AAV-2 hybrid vectors. The notion that AAV-mediated inhibition of adenoviral replication is due predominantly to the expression of the AAV-2 Rep proteins was recently challenged by successful Rep78 expression in a rAd5 vector through recoding of the Rep open reading frame (ORF). We closely analyzed the relative contributions of AAV-2 nucleic acid elements and Rep protein expression to the inhibition of adenoviral replication in both of the above scenarios. When present in\n            <jats:italic>cis<\/jats:italic>\n            , a sequence element in the 3\u2032 part of the\n            <jats:italic>rep<\/jats:italic>\n            gene, comprising only the AAV-2 p40 promoter and the AAV-2 intron sequence, which we termed the RIS-Ad, completely blocks adenoviral replication. p5\/p19 promoter-driven Rep protein expression, on the other hand, only weakly inhibits rAd\/AAV-2 vector propagation, and by inactivation of the RIS-Ad, it is feasible to generate first-generation rAd vectors expressing functional Rep proteins. The RIS-Ad plays no role in the inhibition of adenoviral replication in\n            <jats:italic>trans<\/jats:italic>\n            in a model closely mimicking AAV-2\u2013Ad coinfection. In this case, expression of the Rep proteins is required, as well as the presence of an amplifiable inverted terminal repeat (ITR)-containing template. Thus, very different AAV-2 elements and mechanisms are involved in inhibition of adenoviral replication during rAd\/AAV-2 vector propagation and after Ad-AAV coinfection.\n          <\/jats:p>\n          <jats:p>\n            <jats:bold>IMPORTANCE<\/jats:bold>\n            This is the first study to systematically compare the contributions of AAV-2 protein expression and AAV-2 nucleic acid elements to the inhibition of adenoviral replication in rAd\/AAV-2 hybrid vector generation and in AAV-2\u2013adenovirus coinfection. This study shows that the two inhibitory processes are very different with regard to AAV-2 functions and the mechanisms involved. Whereas inhibition of rAd\/AAV-2 hybrid vector propagation mostly involves a 3\u2032 nucleic acid element in the\n            <jats:italic>rep<\/jats:italic>\n            gene, inhibition of an adenoviral genome in\n            <jats:italic>trans<\/jats:italic>\n            requires the Rep proteins and the AAV ITRs. These findings have important implications both for a basic understanding of the AAV replication cycle and for generation of rAd\/AAV-2 hybrid vectors expressing the nonstructural and structural proteins of AAV-2.\n          <\/jats:p>","DOI":"10.1128\/jvi.02350-14","type":"journal-article","created":{"date-parts":[[2014,10,2]],"date-time":"2014-10-02T08:30:33Z","timestamp":1412238633000},"page":"14126-14137","update-policy":"https:\/\/doi.org\/10.1128\/asmj-crossmark-policy-page","source":"Crossref","is-referenced-by-count":5,"title":["Differential Contribution of Adeno-Associated Virus Type 2 Rep Protein Expression and Nucleic Acid Elements to Inhibition of Adenoviral Replication in\n            <i>cis<\/i>\n            and in\n            <i>trans<\/i>"],"prefix":"10.1128","volume":"88","author":[{"given":"Stefan","family":"Weger","sequence":"first","affiliation":[{"name":"Institute of Virology, Campus Benjamin Franklin, Charit\u00e9 University Medicine Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva","family":"Hammer","sequence":"additional","affiliation":[{"name":"Institute of Virology, Campus Benjamin Franklin, Charit\u00e9 University Medicine Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Regine","family":"Heilbronn","sequence":"additional","affiliation":[{"name":"Institute of Virology, Campus Benjamin Franklin, Charit\u00e9 University Medicine Berlin, Berlin, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"235","reference":[{"key":"e_1_3_2_2_2","doi-asserted-by":"publisher","DOI":"10.1126\/science.149.3685.754"},{"key":"e_1_3_2_3_2","doi-asserted-by":"publisher","DOI":"10.1128\/jvi.40.1.241-247.1981"},{"key":"e_1_3_2_4_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.87.6.2211"},{"key":"e_1_3_2_5_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.93.21.11288"},{"key":"e_1_3_2_6_2","doi-asserted-by":"publisher","DOI":"10.1002\/j.1460-2075.1991.tb04964.x"},{"key":"e_1_3_2_7_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(09)61836-5"},{"key":"e_1_3_2_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrg2988"},{"key":"e_1_3_2_9_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.72.6.5025-5034.1998"},{"key":"e_1_3_2_10_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.14.7163-7173.2002"},{"key":"e_1_3_2_11_2","doi-asserted-by":"publisher","DOI":"10.1089\/10430340252769789"},{"key":"e_1_3_2_12_2","doi-asserted-by":"publisher","DOI":"10.1006\/mthe.2002.0634"},{"key":"e_1_3_2_13_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.96.6.2615"},{"key":"e_1_3_2_14_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ymthe.2004.07.003"},{"key":"e_1_3_2_15_2","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.00779-06"},{"key":"e_1_3_2_16_2","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3301454"},{"key":"e_1_3_2_17_2","first-page":"1","article-title":"Biology of adeno-associated virus","volume":"218","author":"Berns KI","year":"1996","unstructured":"BernsKIGiraudC. 1996. 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J.","family":"Imperiale","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"editor"}]}],"short-title":[],"issued":{"date-parts":[[2014,12,15]]},"references-count":33,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2014,12,15]]}},"alternative-id":["10.1128\/JVI.02350-14"],"URL":"https:\/\/doi.org\/10.1128\/jvi.02350-14","relation":{},"ISSN":["0022-538X","1098-5514"],"issn-type":[{"value":"0022-538X","type":"print"},{"value":"1098-5514","type":"electronic"}],"subject":[],"published":{"date-parts":[[2014,12,15]]},"assertion":[{"value":"2014-08-13","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-09-22","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2014-11-18","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}