HIV-1 accessory proteins VPR and Vif modulate antiviral response by targeting IRF-3 for degradation.
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.
Okumura
Atsushi
A
The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University, Baltimore, MD 21231, USA.
Alce
Tim
T
Lubyova
Barbora
B
Ezelle
Heather
H
Strebel
Klaus
K
Pitha
Paula M
PM
D002460:Cell Line; D015536:Down-Regulation; D015497:HIV-1 / Q000378:metabolism / Q000472:pathogenicity*; D006801:Humans; D050838:Interferon Regulatory Factor-3 / Q000378:metabolism*; D009154:Mutation; D025801:Ubiquitin / Q000378:metabolism*; D054320:vif Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000378:metabolism*
D050838:Interferon Regulatory Factor-3; D025801:Ubiquitin; D054320:vif Gene Products, Human Immunodeficiency Virus; D054325:vpr Gene Products, Human Immunodeficiency Virus