Viral protein U (Vpu): an antagonist of the Tetherin/BST2 restriction factor
The vpu gene is present in the genomes of HIV-1 and some simian immunodeficiency virus (SIV) isolates, such as SIV from chimpanzee (SIVcpz), the immediate precursor of HIV-1 but is absent from HIV-2 and other related SIV’s, such as SIV from sooty mangabey (SIVsm) and SIV from rhesus macaques (SIVmac). HIV-1 vpu encodes a ~81 amino-acids integral class I membrane protein capable of homo- oligomerization. Vpu has been shown to promote the release of HIV-1 virions by counteracting the antiviral activity of a newly identified host restriction factor, called Tetherin/BST2/CD317, that this induced by interferon. Tetherin exerts a potent block on the release of HIV-1 and several other enveloped viruses, by retaining nascent virions at the cell surface via a mechanism whereby the restriction factor directly cross-links virions to the plasma membrane. Vpu antagonizes Tetherin restriction by down-regulating the protein from the cell surface through a mechanism that involves sequestration of the protein into a perinuclear compartment and proteasomal or endo-lysosomal degradation through recruitment of the SCF-β-TrCP E3 ubiquitin ligase. Accumulating evidence suggests that Tetherin represents a significant barrier to primate immunodeficiency lentivirus transmission and may have indeed limited the cross-species transmission of SIVs to human. Importantly, however, the evolutionary acquisition of Vpu-mediated Tetherin antagonism appears to have facilitated the SIV cross-species transmissions that ultimately led to the emergence of pandemic HIV-1 strains. Thus, the dissemination and transmission of HIV-1 and ultimately its pathogenesis are in part intrinsically tied to the biological activities of Vpu.

Our current investigations on Tetherin antagonism by Vpu are aimed at investigating whether Vpu antagonizes the antiviral activity of Tetherin to promote efficient HIV-1 production and transmission.

Some questions addressed in ongoing studies:

• How is Tetherin/BST2 expression transcriptionally regulated in relevant target cells of HIV-1?; What are the host factors involved in its constitutive or IFN-inducible expression; Does HIV infection affects the transcription of Tetherin?
  
• What is the mechanism underlying Tetherin-mediated restriction of retrovirus particle release?
  
• What is the role of Tetherin and Vpu in relevant HIV-1 targets cells?
  
• What is the precise mechanism of Tetherin antagonism by Vpu ?
  
• Can HIV-1 tolerate Tetherin restriction on virus particle release through Vpu-independent mechanism(s)?