Investigation of the roles of Vpr and regulatory T cells in the acute phase HIV-1 infection

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Regulatory CD4+T cells (Tregs) are known for playing a pivotal role in the maintenance of immune homeostasis, and actively cycle in vivo. It is also known that human immunodeficiency virus type 1 (HIV-1) mainly targets CD4+T cells and induces immune activation as a hallmark of HIV-1 pathogenesis. Here, by using a humanized mouse model, we demonstrate that viral protein R (Vpr), a pleiotropic protein encoded by HIV-1, promotes viral expansion by exploiting Tregs during the acute phase of infection. Our findings show that Vpr predominantly causes G2 cell cycle arrest and apoptosis in Tregs, leading to their depletion in vivo. Moreover, we demonstrate that the Treg depletion caused by Vpr induces immune activation, which augments HIV-1 propagation in vivo. Taken together, this is the first report to directly demonstrate that Vpr plays a bifunctional role in HIV-1 replication in vivo by targeting Tregs and suggests that Vpr plays a crucial role in HIV-1 pathogenesis.