Abstract
BackgroundDespite continuing advances in our understanding of AIDS pathogenesis, the mechanism of CD4+ T cell depletion in HIV-1-infected individuals remains unclear. The HIV-1 Vpr accessory protein causes cell death, likely through a mechanism related to its ability to arrest cells in the G2,M phase. Recent evidence implicated the scaffold protein, 14-3-3, in Vpr cell cycle blockade.ResultsWe found that in human T cells, 14-3-3 plays an active role in mediating Vpr-induced cell cycle arrest and reveal a dramatic increase in the amount of Cdk1, Cdc25C, and CyclinB1 bound to 14-3-3 θ during Vprv-induced G2,M arrest. By contrast, a cell-cycle-arrest-dead Vpr mutant failed to augment 14-3-3 θ association with Cdk1 and CyclinB1. Moreover, G2,M arrest caused by HIV-1 infection strongly correlated with a disruption in 14-3-3 θ binding to centrosomal proteins, Plk1 and centrin. Finally, Vpr caused elevated levels of CyclinB1, Plk1, and Cdk1 in a complex with the nuclear transport and spindle assembly protein, importin β.ConclusionThus, our data reveal a new facet of Vpr-induced cell cycle arrest involving previously unrecognized abnormal rearrangements of multiprotein assemblies containing key cell cycle regulatory proteins.ReviewersThis article was reviewed by David Kaplan, Nathaniel R. Landau and Yan Zhou.
Highlights
Despite continuing advances in our understanding of AIDS pathogenesis, the mechanism of CD4+ T cell depletion in HIV-1-infected individuals remains unclear
To determine if 14-3-3 interactions were altered by viral protein R (Vpr) or HIV-1 infection, we examined the association of 14-3-3 θ with Cdk1, CyclinB1, and Cdc25C by co-immunoprecipitation (IP)
(page number not for citation purposes) http://www.biology-direct.com/content/3/1/17 phocytes, we examined Jurkat cells arrested in G2,M by adriamycin [49]. 14-3-3 σ, an isoform not expressed in lymphocytes, binds Cdk1 during G2,M arrest caused by adriamycin in the colorectal cancer cell line HCT116 [21], and there is precedent for such an interaction
Summary
Despite continuing advances in our understanding of AIDS pathogenesis, the mechanism of CD4+ T cell depletion in HIV-1-infected individuals remains unclear. The HIV-1 accessory protein, viral protein R (Vpr), has been shown to be important in viral cytopathicity during virus infection and can kill cells independently when experimentally expressed [1,2]. It is highly conserved, packaged into virions, and facilitates HIV-1 replication in nondividing cells [3], while removal of its homologues in simian immunodeficiency virus results in attenuation of virus replication and disease in rhesus monkeys [4]. Since the majority of these studies (page number not for citation purposes)
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