Abstract
HIV-1 Vpr is a virion-associated protein. Its activities link to viral pathogenesis and disease progression of HIV-infected patients. In vitro, Vpr moderately activates HIV-1 replication in proliferating T cells, but it is required for efficient viral infection and replication in vivo in non-dividing cells such as macrophages. How exactly Vpr contributes to viral replication remains elusive. We show here that Vpr stimulates HIV-1 replication at least in part through its interaction with hHR23A, a protein that binds to 19S subunit of the 26S proteasome and shuttles ubiquitinated proteins to the proteasome for degradation. The Vpr-proteasome interaction was initially discovered in fission yeast, where Vpr was shown to associate with Mts4 and Mts2, two 19S-associated proteins. The interaction of Vpr with the 19S subunit of the proteasome was further confirmed in mammalian cells where Vpr associates with the mammalian orthologues of fission yeast Mts4 and S5a. Consistently, depletion of hHR23A interrupts interaction of Vpr with proteasome in mammalian cells. Furthermore, Vpr promotes hHR23A-mediated protein-ubiquitination, and down-regulation of hHR23A using RNAi significantly reduced viral replication in non-proliferating MAGI-CCR5 cells and primary macrophages. These findings suggest that Vpr-proteasome interaction might counteract certain host restriction factor(s) to stimulate viral replication in non-dividing cells.
Highlights
HIV-1 viral protein R (Vpr) is a virion-associated protein with an average length of 96 amino acids (,15 kD)
Cells expressing GFPVpr had intense green fluorescence at the nuclear rim with little labeling of the cytoplasm (Fig. 1A, top left). This pattern of nuclear membrane localization of Vpr observed in fission yeast cells has been reported previously, which is very similar to that observed in mammalian cells [20,27,32]
We have demonstrated for the first time that Vpr interacts directly with the 26S proteasome
Summary
HIV-1 viral protein R (Vpr) is a virion-associated protein with an average length of 96 amino acids (,15 kD). Vpr displays several distinct activities in host cells, including cytoplasmicnuclear shuttling [1], induction of cell cycle G2 arrest [2] and cell killing [3]. The cell cycle G2 arrest induced by Vpr is thought to suppress human immune functions by preventing T cell clonal expansion [4] and to provide an optimized cellular environment for maximal levels of viral replication [5]. It is unclear at present what is the biological significance of this effect but it may contribute to the depletion of CD4+ T cells in HIV-infected patients [6]. The cytoplasmic-nuclear shuttling is believed to contribute to nuclear transport of the viral pre-integration complex (PIC)[1,7]
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