Transcription factors of the interferon (IFN) regulatory factor (IRF) family have been shown to play an essential role in the regulated expression of type I IFN genes, IFN-stimulated genes (ISG), and other cytokines and chemokines. Three members of the IRF family, IRF-3, IRF-5, and IRF-7, have been identified as acting as direct transducers of virus-mediated signaling. In infected cells, these factors are activated by phosphorylation on the serine residues, transported to the nucleus, where they bind to the promoters of IFNA and IFNB genes and tether histone transacetylases to the transcription complex enhanceosome. IFNB and IFNA subtypes are expressed at different levels in infected cells. The ratio between the relative levels of IRF-3 and IRF-7 was shown to play an essential role in the inducible expression of type I IFN genes, whereas IRF-3 alone is sufficient for expression of the IFNB gene. IRF-5 was identified recently as another inducer of IFNA genes, which has two unique properties: (1) its activation is virus specific, and (2) the profile of IFNA genes induced by IRF-5 is distinct from that induced by IRF-7. Several viruses target functions of IRF to eliminate the early inflammatory response. Kaposi's sarcoma herpesvirus (KSHV) encodes a cluster of four genes with homology to cellular IRF. Three of these vIRF were shown to inhibit induction of IFN genes and ISG in infected cells and function as dominant negative mutants of cellular IRF. The unique properties of previously uncharacterized vIRF-2 and vIRF-3 are discussed.

The activation of IRF-3 during the early stages of viral infection is critical for the initiation of the antiviral response; however the activation of IRF-3 in HIV-1 infected cells has not yet been characterized. We demonstrate that the early steps of HIV-1 infection do not lead to the activation and nuclear translocation of IRF-3; instead, the relative levels of IRF-3 protein are decreased due to the ubiquitin-associated proteosome degradation. Addressing the molecular mechanism of this effect we show that the degradation is independent of HIV-1 replication and that virion-associated accessory proteins Vif and Vpr can independently degrade IRF-3. The null mutation of these two genes reduced the capacity of the HIV-1 virus to down modulate IRF-3 levels. The degradation was associated with Vif- and Vpr-mediated ubiquitination of IRF-3 and was independent of the activation of IRF-3. N-terminal lysine residues were shown to play a critical role in the Vif- and Vpr-mediated degradation of IRF-3. These data implicate Vif and Vpr in the disruption of the initial antiviral response and point to the need of HIV-1 to circumvent the antiviral response during the very early phase of replication.

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