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Orientation-dependent regulation of integrated HIV-1 expression by host gene transcriptional readthrough

Cell Host Microbe. 2008 Aug 14;4(2):134-46. doi: 10.1016/j.chom.2008.06.008.

Abstract

Integrated HIV-1 genomes are found within actively transcribed host genes in latently infected CD4(+) T cells. Readthrough transcription of the host gene might therefore suppress HIV-1 gene expression and promote the latent infection that allows viral persistence in patients on therapy. To address the effect of host gene readthrough, we used homologous recombination to insert HIV-1 genomes in either orientation into an identical position within an intron of an actively transcribed host gene, hypoxanthine-guanine phosphoribosyltransferase (HPRT). Constructs were engineered to permit or block readthrough transcription of HPRT. Readthrough transcription inhibited HIV-1 gene expression for convergently orientated provirus but enhanced HIV-1 gene expression when HIV-1 was in the same orientation as the host gene. Orientation had a >10-fold effect on HIV-1 gene expression. Due to the nature of HIV-1 integration sites in vivo, this orientation-dependent regulation can influence the vast majority of infected cells and adds complexity to the maintenance of latency.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Gene Expression Regulation, Viral*
  • HCT116 Cells
  • HIV Infections / genetics*
  • HIV Infections / virology
  • HIV-1 / genetics*
  • HIV-1 / physiology
  • Histones / genetics
  • Histones / metabolism
  • Host-Pathogen Interactions*
  • Humans
  • Hypoxanthine Phosphoribosyltransferase / genetics
  • Hypoxanthine Phosphoribosyltransferase / metabolism
  • Promoter Regions, Genetic
  • Transcription, Genetic*
  • Virus Integration*
  • Virus Latency

Substances

  • Histones
  • Hypoxanthine Phosphoribosyltransferase