HIV-1 Vpr causes separate cell cycle arrests in G2 and M that activate alternative DNA damage pathways
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Vpr is a conserved primate lentiviral accessory protein that induces cell cycle arrest in G2. The precise mechanism of this arrest and its benefit to viral replication is unknown. Here, we show that in addition to G2 arrest, Vpr from HIV-1/SIVcpz and HIV-2 lineages separately induce mitotic arrest through the spindle assembly checkpoint, in contrast to other Vpr proteins that only cause G2 arrest. The G2 arrest was mediated solely by ATR (ataxia telangiectasia and Rad3 related) and this activity caused elevated cellular dNTP levels. The mitotic arrest required ATM (ataxia-telangiectasia mutated) as well as ATR activity and resulted from the formation of HIV-1 Vpr-induced ultra-fine anaphase bridges. Moreover, ectopic expression of the DNA structure-specific endonuclease, MUS81, prevented mitotic but not G2 arrest. Importantly, virion-incorporated Vpr was sufficient to induce cellular changes within 12h post-infection, implying that these events benefit the early stages of HIV infection.
Author Summary
Vpr is an accessory protein found in primate lentiviruses. Like other retroviral accessory proteins, it is not absolutely required for viral replication but is thought to overcome a cellular factor that negatively regulates infection. The most well-documented effect of Vpr expression is cell cycle arrest in G2. This has been linked to activation of the DNA damage response (DDR) pathway but there are conflicting reports in the literature as to the mechanism behind this. Here, we show that Vpr from some lentiviruses, in fact, cause two separate cell cycle blocks, in G2 and M, that require different DDR pathways. Other Vpr proteins only cause arrest in G2. Furthermore, we show that degradation of one reported target of Vpr, MUS81, is specifically linked to M but not G2 arrest. This indicates that not all Vpr functions are conserved and helps explain contradictory published results. Additionally, we found that virion-incorporated Vpr protein was able to induce cellular changes, including elevated dNTP levels, within 12 hours of infection suggesting that these events enhance early HIV-1 replication events.
