Abstract
Primate lentiviruses have evolved sophisticated strategies to suppress the immune response of their host species. For example, HIV-2 and most simian immunodeficiency viruses (SIVs) use their accessory protein Nef to prevent T cell activation and antiviral gene expression by downmodulating the T cell receptor CD3. This Nef function was lost in HIV-1 and other vpu-encoding viruses suggesting that the acquisition of Vpu-mediated NF-κB inhibition reduced the selection pressure for inhibition of T cell activation by Nef. To obtain further insights into the modulation of NF-κB activity by primate lentiviral accessory factors, we analyzed 32 Vpr proteins from a large panel of divergent primate lentiviruses. We found that those of SIVcol and SIVolc infecting Colobinae monkeys showed the highest efficacy in suppressing NF-κB activation. Vpr-mediated inhibition of NF-κB resulted in decreased IFNβ promoter activity and suppressed type I IFN induction in virally infected primary cells. Interestingly, SIVcol and SIVolc differ from all other primate lentiviruses investigated by the lack of both, a vpu gene and efficient Nef-mediated downmodulation of CD3. Thus, primate lentiviruses have evolved at least three alternative strategies to inhibit NF-κB-dependent immune activation. Functional analyses showed that the inhibitory activity of SIVolc and SIVcol Vprs is independent of DCAF1 and the induction of cell cycle arrest. While both Vprs target the IKK complex or a factor further downstream in the NF-κB signaling cascade, only SIVolc Vpr stabilizes IκBα and inhibits p65 phosphorylation. Notably, only de-novo synthesized but not virion-associated Vpr suppressed the activation of NF-κB, thus enabling NF-κB-dependent initiation of viral gene transcription during early stages of the replication cycle, while minimizing antiviral gene expression at later stages. Our findings highlight the key role of NF-κB in antiviral immunity and demonstrate that primate lentiviruses follow distinct evolutionary paths to modulate NF-κB-dependent expression of viral and antiviral genes.
Highlights
Cells are equipped with a plethora of pattern recognition receptors (PRRs) that induce an antiviral immune response upon sensing of patterns associated with viral infection
The cellular transcription factor NF-κB plays a complex role in the lentiviral replication cycle
Primate lentiviruses tightly regulate the activation of NF-κB throughout their replication cycle to enable transcription of viral genes while minimizing antiviral gene expression
Summary
Cells are equipped with a plethora of pattern recognition receptors (PRRs) that induce an antiviral immune response upon sensing of patterns associated with viral infection. Once efficient and stable viral transcription is ensured by the viral Tat protein, the late protein Vpu inhibits the activation of NF-κB in a dominant manner to suppress expression of type I IFNs, restriction factors and other antiviral genes [6]. This inhibitory effect on NF-κB is highly conserved among primate lentiviral Vpu proteins [6,8], suggesting an important role in vivo. HIV-2 and most SIVs employ an alternative strategy and suppress T cell activation and NF-κB
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