HIV-1 accessory proteins VPR and Vif modulate antiviral response by targeting IRF-3 for degradation

• Published in: Virology (New York, N.Y.) Vol. 373; no. 1; pp. 85 - 97
• Main Authors: Okumura, Atsushi, Alce, Tim, Lubyova, Barbora, Ezelle, Heather, Strebel, Klaus, Pitha, Paula M
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.03.2008
• Subjects: 60 APPLIED LIFE SCIENCES; AIDS VIRUS; Antiviral response; Cell Line; DNA; Down-Regulation; GENES; HIV-1; HIV-1 - metabolism; HIV-1 - pathogenicity; Human immunodeficiency virus 1; Humans; Infectious Disease; INTERFERON; Interferon regulatory factor 3 (IRF-3); Interferon Regulatory Factor-3 - metabolism; LEUKOCYTES; LYSINE; Mutation; MUTATIONS; NEWCASTLE DISEASE; TRANSLOCATION; Ubiquitin - metabolism; URACILS; Vif; vif Gene Products, Human Immunodeficiency Virus - genetics; vif Gene Products, Human Immunodeficiency Virus - metabolism; Vpr; vpr Gene Products, Human Immunodeficiency Virus - genetics; vpr Gene Products, Human Immunodeficiency Virus - metabolism; HIV-1; NDV; Antiviral response; SeV; Sendai virus; Uracil DNA glycosylase; PBMC; Peripheral blood leucocytes; UNG; Interferon regulatory factor 3 (IRF-3); Vif; Azidothymidine; Interferon stimulated gene; Vpr; Interferon; Newcastle disease virus; AZT; ISG
• ISSN: 0042-6822; 1096-0341
• DOI: 10.1016/j.virol.2007.10.042

Abstract 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.