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

Y Han, YB Lin, W An, J Xu, HC Yang, K O'Connell… - Cell host & …, 2008 - cell.com
Y Han, YB Lin, W An, J Xu, HC Yang, K O'Connell, D Dordai, JD Boeke, JD Siliciano
Cell host & microbe, 2008cell.com
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 …
Summary
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.
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