tailieunhanh - Báo cáo y học: "Vpu serine 52 dependent counteraction of tetherin is required for HIV-1 replication in macrophages, but not in ex vivo human lymphoid tissue"

Tuyển tập các báo cáo nghiên cứu về y học được đăng trên tạp chí y học Retrovirology cung cấp cho các bạn kiến thức về ngành y đề tài: "Vpu serine 52 dependent counteraction of tetherin is required for HIV-1 replication in macrophages, but not in ex vivo human lymphoid tissue. | Schindler et al. Retrovirology 2010 7 1 http content 7 1 1 RETR0VIR0L0GY RESEARCH Open Access Vpu serine 52 dependent counteraction of tetherin is required for HIV-1 replication in macrophages but not in ex vivo human lymphoid tissue Michael Schindler 1 Devi Rajan2 3 Carina Banning1 Peter Wimmer1 Herwig Koppensteiner1 Alicja Iwanski1 Anke Specht2 Daniel Sauter2 Thomas Dobner1 Frank Kirchhoff2 Abstract Background The human immunodeficiency virus type 1 HIV-1 Vpu protein degrades CD4 and counteracts a restriction factor termed tetherin CD317 Bst-2 to enhance virion release. It has been suggested that both functions can be genetically separated by mutation of a serine residue at position 52. However recent data suggest that the S52 phosphorylation site is also important for the ability of Vpu to counteract tetherin. To clarify this issue we performed a comprehensive analysis of HIV-1 with a mutated casein kinase-II phosphorylation site in Vpu in various cell lines primary blood lymphocytes PBL monocyte-derived macrophages MDM and ex vivo human lymphoid tissue HLT . Results We show that mutation of serine 52 to alanine S52A entirely disrupts Vpu-mediated degradation of CD4 and strongly impairs its ability to antagonize tetherin. Furthermore casein-kinase II inhibitors blocked the ability of Vpu to degrade tetherin. Overall Vpu S52A could only overcome low levels of tetherin and its activity decreased in a manner dependent on the amount of transiently or endogenously expressed tetherin. As a consequence the S52A Vpu mutant virus was unable to replicate in macrophages which express high levels of this restriction factor. In contrast HIV-1 Vpu S52A caused CD4 T-cell depletion and spread efficiently in ex vivo human lymphoid tissue and PBL most likely because these cells express comparably low levels of tetherin. Conclusion Our data explain why the effect of the S52A mutation in Vpu on virus release is cell-type dependent and suggest that a reduced .