HIV infection of dendritic cells subverts the IFN induction pathway via IRF-1 and inhibits type 1 IFN production

Andrew Harman, Joey Lai, Stuart Turville, Shamith Samarajiwa, Lachlan Robert Gray, Valerie Marsden, Sarah Mercier, Kate Jones, Najla Nasr, Arjun Rustagi, Helen Cumming, Heather Donaghy, Johnson Mak, Michael Gale Jr, Melissa Churchill, Paul Hertzog, Anthony Cunningham

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Abstract

Many viruses have developed mechanisms to evade the IFN response. Here, HIV-1 was shown to induce a distinct subset of IFN-stimulated genes (ISGs) in monocyte-derived dendritic cells (DCs), without detectable type I or II IFN. These ISGs all contained an IFN regulatory factor 1 (IRF-1) binding site in their promoters, and their expression was shown to be driven by IRF-1, indicating this subset was induced directly by viral infection by IRF-1. IRF-1 and -7 protein expression was enriched in HIV p24 antigen-positive DCs. A HIV deletion mutant with the IRF-1 binding site deleted from the long terminal repeat showed reduced growth kinetics. Early and persistent induction of IRF-1 was coupled with sequential transient up-regulation of its 2 inhibitors, IRF-8, followed by IRF-2, suggesting a mechanism for IFN inhibition. HIV-1 mutants with Vpr deleted induced IFN, showing that Vpr is inhibitory. However, HIV IFN inhibition was mediated by failure of IRF-3 activation rather than by its degradation, as in T cells. In contrast, herpes simplex virus type 2 markedly induced IFNbeta and a broader range of ISGs to higher levels, supporting the hypothesis that HIV-1 specifically manipulates the induction of IFN and ISGs to enhance its noncytopathic replication in DCs.
Original languageEnglish
Pages (from-to)298 - 308
Number of pages11
JournalBlood
Volume118
Issue number2
DOIs
Publication statusPublished - 2011

Cite this

Harman, A., Lai, J., Turville, S., Samarajiwa, S., Gray, L. R., Marsden, V., Mercier, S., Jones, K., Nasr, N., Rustagi, A., Cumming, H., Donaghy, H., Mak, J., Gale Jr, M., Churchill, M., Hertzog, P., & Cunningham, A. (2011). HIV infection of dendritic cells subverts the IFN induction pathway via IRF-1 and inhibits type 1 IFN production. Blood, 118(2), 298 - 308. https://doi.org/10.1182/blood-2010-07-297721