title: Integrase inhibitor reversal dynamics indicate unintegrated HIV-1 dna initiate de novo integration.
abstract: BACKGROUND
  Genomic integration, an obligate step in the HIV-1 replication cycle, is blocked by the integrase inhibitor raltegravir. A consequence is an excess of unintegrated viral DNA genomes, which undergo intramolecular ligation and accumulate as 2-LTR circles. These circularized genomes are also reliably observed in vivo in the absence of antiviral therapy and they persist in non-dividing cells. However, they have long been considered as dead-end products that are not precursors to integration and further viral propagation.
  
  
  RESULTS
  Here, we show that raltegravir action is reversible and that unintegrated viral DNA is integrated in the host cell genome after raltegravir removal leading to HIV-1 replication. Using quantitative PCR approach, we analyzed the consequences of reversing prolonged raltegravir-induced integration blocks. We observed, after RAL removal, a decrease of 2-LTR circles and a transient increase of linear DNA that is subsequently integrated in the host cell genome and fuel new cycles of viral replication.
  
  
  CONCLUSIONS
  Our data highly suggest that 2-LTR circles can be used as a reserve supply of genomes for proviral integration highlighting their potential role in the overall HIV-1 replication cycle.
authors: Sylvain
authors: S
authors: Thierry
authors: Soundasse
authors: S
authors: Munir
authors: Eloïse
authors: E
authors: Thierry
authors: Frédéric
authors: F
authors: Subra
authors: Hervé
authors: H
authors: Leh
authors: Alessia
authors: A
authors: Zamborlini
authors: Dyana
authors: D
authors: Saenz
authors: David N
authors: DN
authors: Levy
authors: Paul
authors: P
authors: Lesbats
authors: Ali
authors: A
authors: Saïb
authors: Vincent
authors: V
authors: Parissi
authors: Eric
authors: E
authors: Poeschla
authors: Eric
authors: E
authors: Deprez
authors: Olivier
authors: O
authors: Delelis
mesh_terms: D002460:Cell Line; D004279:DNA, Viral / Q000378:metabolism*; D019427:HIV Integrase / Q000378:metabolism*; D019428:HIV Integrase Inhibitors / Q000378:metabolism; D015497:HIV-1 / Q000201:enzymology / Q000502:physiology*; D006801:Humans; D060888:Real-Time Polymerase Chain Reaction; D016662:Virus Integration; D014779:Virus Replication
chemical_list: D004279:DNA, Viral; D019428:HIV Integrase Inhibitors; D019427:HIV Integrase; C514801:p31 integrase protein, Human immunodeficiency virus 1