Integrase inhibitor reversal dynamics indicate unintegrated HIV-1 dna initiate de novo integration

Sylvain Thierry, Soundasse Munir, Eloïse Thierry, Frédéric Subra, Hervé Leh, Alessia Zamborlini, Dyana Saenz, David N. Levy, Paul Lesbats, Ali Saïb, Vincent Parissi, Eric Poeschla, Eric Deprez, Olivier Delelis

Research output: Contribution to journalArticle

30 Scopus citations

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.

Original languageEnglish (US)
Article number24
JournalRetrovirology
Volume12
Issue number1
DOIs
StatePublished - Mar 12 2015

Keywords

  • 2-LTR circles
  • Integrase
  • Strand-transfer inhibitors
  • Unintegrated viral DNA

ASJC Scopus subject areas

  • Virology
  • Infectious Diseases

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    Thierry, S., Munir, S., Thierry, E., Subra, F., Leh, H., Zamborlini, A., Saenz, D., Levy, D. N., Lesbats, P., Saïb, A., Parissi, V., Poeschla, E., Deprez, E., & Delelis, O. (2015). Integrase inhibitor reversal dynamics indicate unintegrated HIV-1 dna initiate de novo integration. Retrovirology, 12(1), [24]. https://doi.org/10.1186/s12977-015-0153-9