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Mechanistic study of BST-2 down-modulation by HIV-1 Vpu


Mammals encode proteins that inhibit viral replication at the cellular level. In turn, certain viruses have evolved genes that can counteract these intrinsic restrictions. Human BST-2 (bone marrow stromal cell antigen 2, also named CD317/HM1.24/tetherin) is recently identified an IFN-induced antiviral protein that blocks release of human immunodeficiency virus type 1 (HIV-1) from the cell surface. This antiviral activity of BST-2 is counteracted by HIV-1 Vpu. Our group as well as the others have generated data showing that Vpu antagonizes human BST-2 (hBST2) but not BST-2 from African green monkeys (agm BST-2).

Methods and Results

Through mutagenesis study, we have mapped the determinants of sensitivity to Vpu to several sites within the transmembrane domain of agmBST-2, with deletion of the 22-LL-23 residues conferring the highest degree of resistance to Vpu. This resistance activity is further shown as a result of a weak association of agmBST-2 or the hΔLL22/23 mutant with Vpu and a refraction of these BST-2 proteins to down-modulation by Vpu. With the aim of assessing the involvement of the proteasome and the lysosome degradation pathways in Vpu-mediated down-modulation of hBST-2, specific proteasome inhibitors and lysosome inhibitors were tested for their ability of rescuing hBST-2 expression in the presence of Vpu. The results show that the proteasome inhibitors ALLN and MG132 restore hBST-2 expression to the control level, whereas, lysosome inhibitors chloroquine (CQ) or bafilomycin A1 (BafA1) partially blocks down-modulation of hBST2 by Vpu. To determine whether ubiquitination serves as the signal that triggers hBST-2 down-modulation, we first co-transfected the HA-ubiquitin DNA together with hBST-2 DNA in the presence or absence of Vpu. A specific HA-ubiquitin signal was not observed for hBST-2 with Vpu expression. Moreover, when the only two lysine residues (K18 and K21) within the cytoplasmic domain of hBST-2 were mutated, the K(18,21)R mutant is still sensitive to Vpu-induced down-modulation and is unable to restrict production of wild type HIV-1.


Taken together, our results suggest that Vpu triggers hBST-2 down-modulation mainly through the proteasome pathway. The down-modulation event may be triggered by signals other than direct ubiquitination of hBST-2.

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Open Access This article is published under license to BioMed Central Ltd. This is an Open Access article is distributed under the terms of the Creative Commons Attribution 2.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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Zhang, J., Rong, L., Wainberg, M.A. et al. Mechanistic study of BST-2 down-modulation by HIV-1 Vpu. Retrovirology 6 (Suppl 2), P97 (2009).

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