An HIV-1 replication pathway utilizing reverse transcription products that fail to integrate

Benjamin Trinité, Eric C. Ohlson, Igor Voznesensky, Shashank P. Rana, Chi N. Chan, Saurabh Mahajan, Jason Alster, Sean A. Burke, Dominik Wodarz, David N. Levy

Research output: Contribution to journalArticlepeer-review

Abstract

Integration is a central event in the replication of retroviruses, yet≥90% of HIV-1 reverse transcripts fail to integrate, resulting in accumulation of unintegrated viral DNA in cells. However, understanding what role, if any, unintegrated viral DNA plays in the natural history of HIV-1 has remained elusive. Unintegrated HIV-1 DNA is reported to possess a limited capacity for gene expression restricted to early gene products and is considered a replicative dead end. Although the majority of peripheral blood CD4+T cells are refractory to infection, nonactivated CD4+T cells present in lymphoid and mucosal tissues are major targets for infection. Treatment with cytokine interleukin-2 (IL-2), IL-4, IL-7, or IL-15 renders CD4+T cells permissive to HIV-1 infection in the absence of cell activation and proliferation and provides a useful model for infection of resting CD4+T cells. We found that infection of cytokine-treated resting CD4+T cells in the presence of raltegravir or with integrase active-site mutant HIV-1 yielded de novo virus production following subsequent T cell activation. Infection with integration-competent HIV-1 naturally generated a population of cells generating virus from unintegrated DNA. Latent infection persisted for several weeks and could be activated to virus production by a combination of a histone deacetylase inhibitor and a protein kinase C activator or by T cell activation. HIV-1 Vpr was essential for unintegrated HIV-1 gene expression and de novo virus production in this system. Bypassing integration by this mechanism may allow the preservation of genetic information that otherwise would be lost.

Original languageEnglish (US)
Pages (from-to)12701-12720
Number of pages20
JournalJournal of virology
Volume87
Issue number23
DOIs
StatePublished - Dec 2013

ASJC Scopus subject areas

  • Microbiology
  • Immunology
  • Insect Science
  • Virology

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