Epigenetic activation of unintegrated HIV-1 genomes by gut-associated short chain fatty acids and its implications for HIV infection.

Journal Article (Journal Article)

Integration of HIV-1 linear DNA into the host chromatin is an essential step in the viral life cycle. However, the majority of reverse-transcribed, nuclear-imported viral genomes remain episomal, either as linear or circular DNA. To date, these nonintegrated viral genomes are largely considered "dead-end products" of reverse transcription. Indeed, limited gene expression from nonintegrated HIV-1 has been reported, although the mechanism that renders nonintegrating HIV-1 genomes incapable of supporting efficient viral replication has not been fully elucidated. Here, we demonstrate that nonintegrating HIV-1 and HIV-1-based vector genomes are organized into chromatin structures and enriched with histone modifications typical of transcriptionally silenced chromatin. Gene expression and replication of nonintegrating HIV-1 was notably increased in vitro upon exposure to histone deacetylase inhibitors (HDACi) in the form of various short-chain fatty acids (SCFAs) known to be endogenously produced by normal microbial-gut flora. Furthermore, we demonstrated genetic and functional crosstalk between episomal and integrated vector/viral genomes, resulting in recombination between integrated and nonintegrated HIV-1, as well as mobilization of episomal vector genomes by productive viral particles encoded by integrated viral genomes. Finally, we propose a mechanism describing the role of episomal HIV-1 forms in the viral life cycle in a SCFA-rich gut environment.

Full Text

Duke Authors

Cited Authors

  • Kantor, B; Ma, H; Webster-Cyriaque, J; Monahan, PE; Kafri, T

Published Date

  • November 3, 2009

Published In

Volume / Issue

  • 106 / 44

Start / End Page

  • 18786 - 18791

PubMed ID

  • 19843699

Pubmed Central ID

  • PMC2773968

Electronic International Standard Serial Number (EISSN)

  • 1091-6490

Digital Object Identifier (DOI)

  • 10.1073/pnas.0905859106

Language

  • eng

Conference Location

  • United States