HIV-1 Vpr activates both canonical and noncanonical NF-κB pathway by enhancing the phosphorylation of IKKα/β

The human immunodeficiency virus type I (HIV-1) Vpr plays an essential role in viral replication. A number of studies have reported that Vpr modulates the nuclear factor-κB (NF-κB) pathway. Yet, the reported effects of Vpr on NF-κB signaling are controversial. In this study, we investigate the interplay between Vpr and NF-κB pathway. We discover that HIV-1 infection elevates the phosphorylation of IκBα and p100, and that this increase is greatly reduced when a Vpr-negative HIV-1 is used for infection. Our data further show that Vpr regulates the activity of IKKα/β through interactions. In addition, Vpr modulates the phosphorylation of p65 and p100, suggesting that Vpr activates both canonical and noncanonical NF-κB pathway. Knock down of endogenous IKKα/β result in a decrease in Vpr-mediated NF-κB and HIV-1 LTR activation. Given that Vpr is present in HIV-1 particles, our data suggest that Vpr activates the NF-κB pathway immediately after HIV-1 entry.

► Vpr, in the context of HIV-1 infection, promotes the activation of IκBα and p100.
► Vpr activates both canonical and noncanonical NF-κB pathway.
► We discover that Vpr regulates the activity of IKKα/β through direct interactions.
► Endogenous IKKα and IKKβ are indispensable for Vpr-mediated NF-κB activation.