Efficient BST2 antagonism by Vpu is critical for early HIV-1 dissemination in humanized mice

Abstract

BackgroundVpu is a multifunctional accessory protein that enhances the release of HIV-1 by counteracting the entrapment of nascent virions on infected cell surface mediated by BST2/Tetherin. Vpu-mediated BST2 antagonism involves physical association with BST2 and subsequent mislocalization of the restriction factor to intracellular compartments followed by SCF(β-TrCP) E3 ligase-dependent lysosomal degradation. Apart from BST2 antagonism, Vpu also induces down regulation of several immune molecules, including CD4 and SLAMF6/NTB-A, to evade host immune responses and promote viral dissemination. However, it should be noted that the multiple functions of Vpu have been studied in cell-based assays, and thus it remains unclear how Vpu influences the dynamic of HIV-1 infection in in vivo conditions.ResultsUsing a humanized mouse model of acute infection as well as CCR5-tropic HIV-1 that lack Vpu or encode WT Vpu or Vpu with mutations in the β-TrCP binding domain, we provide evidence that Vpu-mediated BST2 antagonism plays a crucial role in establishing early plasma viremia and viral dissemination. Interestingly, we also find that efficient HIV-1 release and dissemination are directly related to functional strength of Vpu in antagonizing BST2. Thus, reduced antagonism of BST2 due to β-TrCP binding domain mutations results in decreased plasma viremia and frequency of infected T cells, highlighting the importance of Vpu-mediated β-TrCP-dependent BST-2 degradation for optimal initial viral propagation.ConclusionsOverall, our findings suggest that BST2 antagonism by Vpu is critical for efficient early viral expansion and dissemination during acute infection and as such is likely to confer HIV-1 increased transmission fitness.

Differential Control of BST2 Restriction and Plasmacytoid Dendritic Cell Antiviral Response by Antagonists Encoded by HIV-1 Group M and O Strains

“…This attribute of O-Nef proteins may be responsible for the inefficient viral spread observed in vitro under conditions of limiting virus input. Previous studies using humanized mice suggested that BST2 antagonism by Vpu facilitated HIV-1 replication and propagation in vivo, in particular during early stages following infection, where transmission by cell-free virus may play a critical role (4,5). In contrast to M-Vpu, O-Nef may not be effective at promoting the initial burst of viral proliferation and expansion that is most likely necessary to enable dissemination to local lymphoid tissues and the establishment of systemic infection (49).…”

Three-Dimensional Structural Characterization of HIV-1 Tethered to Human Cells

“…HIV-1 is able to circumvent tetherinmediated entrapment through the disruption of tetherin trafficking by the viral protein Vpu. Vpu antagonism of tetherin has been implicated in viral expansion and dissemination in vivo (18)(19)(20)(21).…”

HIV-1 Vpu Downmodulates ICAM-1 Expression, Resulting in Decreased Killing of Infected CD4 + T Cells by NK Cells

“…All transmitter/founder (T/F) HIV-1 strains contain a functionally competent vpu coding sequence (3), and humanized mouse models have demonstrated the contribution of Vpu to early viral dissemination after infection (4,5).…”