Retroviruses and Novel Drugs

Biography

Biography: Shan Cen

Abstract

Background: BST-2(Tetherin/CD317) has been recently recognized as a potent restriction factor that inhibits the release of HIV-1 particles from infected cells. HIV-1 Vpu induces the degradation of BST-2 and allows virus escape from the restriction. Therefore, blocking Vpu-mediated down-regulation of cell surface BST-2 provides clearly an opportunity for developing anti-HIV-1 drugs. Method: In this study, a cell-based ELISA assay was used to screen for small molecule compounds that restore cell surface BST-2 in the presence of Vpu. Co-IP, BRET, cell image and other techniques were performed to study the mechanism of positive compounds. Results: In this study, we identified two small molecule compounds IMB-AZ and IMB-LA, both of which can restore cell surface BST-2 in a Vpu-dependent manner. Interestingly, the compounds had no effect on the degradation of IFNAR1 induced by IFN, suggesting that their abilities to block BST-2 degradation most unlikely resulted from a general inhibition of lysosome degradation pathway. Mechanism study revealed that IMB-AZ specifically inhibit Vpu-induced ubiquitination of BST-2 without interrupting the formation of Vpu-β-TrCP complex. Unlike IMB-AZ, the treatment of IMB-LA resulted in accumulation of BST-2 within CD63-containing endosomal compartments, suggesting that IMB-LA may impair the translocalization of BST-2 to lysosomes，and consequently inhibit the degradation of BST-2. Furthermore, the results of viral infectivity assay demonstrated that both of IMB-AZ and IMB-LA inhibit the release of HIV-1 particles and the infectivity of progeny virions in cell lines expressing BST-2. Conclusion: In summary, results herein demonstrated that both of IMB-AZ and IMB-LA could specifically inhibit the degradation of BST-2 induced by Vpu, and impair HIV-1 replication in a BST-2 dependent manner, suggesting IMB-AZ and IMB-LA have potent potential to develop a new anti-HIV drug.