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Mutations in the 3'-PPT Lead to HIV-1 Replication without Integration

dc.rights.licenseopenen_US
dc.contributor.authorRICHETTA, Clémence
dc.contributor.authorSUBRA, Frédéric
dc.contributor.authorMALET, Isabelle
dc.contributor.authorLEH, Hervé
dc.contributor.authorCHARPENTIER, Charlotte
dc.contributor.authorCORONA, Angela
dc.contributor.authorCOLLIN, Gilles
dc.contributor.authorDESCAMPS, Diane
dc.contributor.authorDEPREZ, Eric
hal.structure.identifierMicrobiologie Fondamentale et Pathogénicité [MFP]
dc.contributor.authorPARISSI, Vincent
dc.contributor.authorCALVEZ, Vincent
dc.contributor.authorTRAMONTANO, Enzo
dc.contributor.authorMARCELIN, Anne-Geneviève
dc.contributor.authorDELELIS, Olivier
dc.date.accessioned2023-05-15T07:57:58Z
dc.date.available2023-05-15T07:57:58Z
dc.date.issued2022-06-27
dc.identifier.issn0022-538Xen_US
dc.identifier.urihttps://oskar-bordeaux.fr/handle/20.500.12278/182112
dc.description.abstractEnIntegration of the reverse-transcribed genome is a critical step of the retroviral life cycle. Strand-transfer inhibitors (INSTIs) used for antiretroviral therapy inhibit integration but can lead to resistance mutations in the integrase gene, the enzyme involved in this reaction. A significant proportion of INSTI treatment failures, particularly those with second-generation INSTIs, show no mutation in the integrase gene. Here, we show that replication of a selected dolutegravir-resistant virus with mutations in the 3'-PPT (polypurine tract) was effective, although no integrated viral DNA was detected, due to the accumulation of unintegrated viral DNA present as 1-LTR circles. Our results show that mutation in the 3'-PPT leads to 1-LTR circles and not linear DNA as classically reported. In conclusion, our data provide a molecular basis to explain a new mechanism of resistance to INSTIs, without mutation of the integrase gene and highlights the importance of unintegrated viral DNA in HIV-1 replication. IMPORTANCE Our work highlights the role of HIV-1 unintegrated viral DNA in viral replication. A virus, resistant to strand-transfer inhibitors, has been selected in vitro. This virus highlights a mutation in the 3'PPT region and not in the integrase gene. This mutation modifies the reverse transcription step leading to the accumulation of 1-LTR circles and not the linear DNA. This accumulation of 1-LTR circles leads to viral replication without integration of the viral genome.
dc.language.isoENen_US
dc.subject.enHIV-1
dc.subject.enintegrase
dc.subject.enintegration
dc.subject.enresistance
dc.subject.enunintegrated viral DNA
dc.title.enMutations in the 3'-PPT Lead to HIV-1 Replication without Integration
dc.typeArticle de revueen_US
dc.identifier.doi10.1128/jvi.00676-22en_US
dc.subject.halSciences du Vivant [q-bio]en_US
bordeaux.journalJournal of Virologyen_US
bordeaux.volume96en_US
bordeaux.hal.laboratoriesMFP (Laboratoire Microbiologie Fondamentale et Pathogénicité) - UMR 5234en_US
bordeaux.institutionCNRSen_US
bordeaux.peerReviewedouien_US
bordeaux.inpressnonen_US
bordeaux.import.sourcehal
hal.identifierhal-03826878
hal.version1
hal.exportfalse
workflow.import.sourcehal
dc.rights.ccPas de Licence CCen_US
bordeaux.COinSctx_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.jtitle=Journal%20of%20Virology&rft.date=2022-06-27&rft.volume=96&rft.eissn=0022-538X&rft.issn=0022-538X&rft.au=RICHETTA,%20Cl%C3%A9mence&SUBRA,%20Fr%C3%A9d%C3%A9ric&MALET,%20Isabelle&LEH,%20Herv%C3%A9&CHARPENTIER,%20Charlotte&rft.genre=article


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