Article

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

Centre for Virus Research, Westmead Millennium Institute, Westmead, Australia.
Blood (Impact Factor: 10.45). 03/2011; 118(2):298-308. DOI: 10.1182/blood-2010-07-297721
Source: PubMed

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 IFNβ 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.

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Available from: Paul J Hertzog, Jun 25, 2014
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    • "However, we do know that the HIV gene and protein product Vpr inhibits type I IFN production, and that signalling through CCR5 and components of the HIV inoculum might induce maturation and migration. HIV nucleic acids might interact with cytoplasmic RNA or DNA sensors to induce these changes (Anand et al, 2009; Cunningham et al, 2013; Harman et al, 2011). The paper by Cavarelli et al. extends our knowledge of such mechanisms. "

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    • "In contrast to other RNA viruses such as measles and influenza infection (Zilliox et al., 2006), HIV-1 infection, and other retroviruses also, do not induce type I IFN responses in DC (Luban, 2012). As regards to the mechanism, IRF-3, a pathogen-sensing pathway component, was shown to be depleted in HIV-infected T cells (Doehle et al., 2009) but not in DC, whereas Vpr-dependent inhibition of IRF-3 nuclear translocation was reported to occur in DC (Harman et al., 2011). The stimulation of DNA- and/or RNA-sensing pathway by Vpx may overcome this Vpr effect in DCs. "
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    • "However, we do know that the HIV gene and protein product Vpr inhibits type I IFN production, and that signalling through CCR5 and components of the HIV inoculum might induce maturation and migration. HIV nucleic acids might interact with cytoplasmic RNA or DNA sensors to induce these changes (Anand et al, 2009; Cunningham et al, 2013; Harman et al, 2011). The paper by Cavarelli et al. extends our knowledge of such mechanisms. "

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