The accessory protein Vpr of Human Immunodeficiency Virus type 1 (HIV-1) enhances replication of the virus in macrophages. Virus particle packaged Vpr is released in target cells shortly after entry, suggesting it is required early in infection. Why it is required for infection of macrophages and not cycling T-cells and why it induces G2/M arrest in cycling cells are unknown. Here we observe, by co-immunoprecipitation assay, an interaction between Vpr and endogenous REAF (RNA-associated Early-stage Antiviral Factor, RPRD2), a protein shown previously to potently restrict HIV infection. After HIV-1 infects macrophages, within 30 min of viral entry, Vpr induces the degradation of REAF. Subsequently, as replication continues, REAF expression is upregulated – a response which is curtailed by Vpr. REAF is more highly expressed in differentiated macrophages than in cycling T-cells. Expression in cycling cells is cell-cycle dependent and knockdown induces cell-cycle perturbation. Therefore, our results support the long held hypothesis that Vpr induces the degradation of a factor involved in the cell cycle that impedes HIV infection in macrophages.

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