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

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.

HIV-1 Vpu Accessory Protein Induces Caspase-mediated Cleavage of IRF3 Transcription Factor

“…Additionally, we investigated a possible contribution of Vpr and Vif because these proteins can induce degradation of IRF3 (16). Jurkat cells were infected with either WT or Vpu-, Vpr-, or Vif-null mutant pseudotyped HIV-1 for 48 h. As expected, infection with Vpunull HIV-1 elicited less IRF3 and PARP cleavage than its WT counterpart (Fig.…”

“…Vpr and Vif were already known to modulate the antiviral response through degradation of IRF3 (16). In addition, monocyte-derived dendritic cells infected with Vpr-null HIV-1 (although not Vif-null HIV-1) were shown to exhibit increased IFN␤ mRNA expression (15).…”

“…Because of the blunted anti-viral response to HIV-1, it has been suggested that this virus might have a mechanism to antagonize IRF3 function. Indeed, two other HIV-1 accessory proteins, Vif and Vpr, impair the innate immune response by promoting degradation of IRF3 (16). Recently, Vpu was shown to induce lysosomal degradation of IRF3 (17), although this finding was challenged by another study (18).…”

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

“…It will be interesting to further explore a potential antiviral role of HLTF in other nondividing cells such as dendritic cells and in primary lymphocytes. One alternative and non-mutually exclusive possibility is that HLTF degradation is related to the ability of Vpr to interfere with the immune response and the cooperation between immune cells (77)(78)(79)(80)(81) is related to the ability of Vpr to escape or promote immune detection in primary cells should be investigated. A role of HLTF in DNA sensing could be a consequence of its capacity to bind ssDNA ends (82).…”

Viral surface glycoproteins, gp120 and gp41, as potential drug targets against HIV-1: Brief overview one quarter of a century past the approval of zidovudine, the first anti-retroviral drug

“…Vif may either increase viral infectivity or may allow productive infections of otherwise non-permissive cell types [47]. Vpr functions early in the viral life cycle, most likely in transport of the viral genome to the nucleus [48]. Vpu enhances virus budding and degrades cellular CD4 [49].…”