This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The overall goal of this project is to understand the role of the HIV-1 protein Vpu in HIV pathogenesis. The original aim was to understand how Vpu modulates expression of the cytokine receptor CD40. Our studies showed that Vpu's effect on CD40 was due to downstream modulation of other pathways. We thus performed proteomics to identify novel cellular proteins affected by Vpu in a beta TrCP-dependent manner, and identified BST-2 as a significant Vpu target. This was important, since BST-2, was recently identified as a host antiviral factor that restricts the release of HIV from infected cells. BST-2 was renamed tetherin and independent studies confirmed our finding that Vpu antagonizes BST-2. We thus refocused our project goals to investigate the mechanisms and biological consequences of Vpu-mediated BST-2 downregulation and have made significant progress in this regards. We found that Vpu interacts with and targets BST-2 for degradation by an endosomal/lysosomal pathway and that beta TrCP is required for degradation and have published this work. We have made additional progress in the following areas i) mapping Vpu regions necessary for overcoming BST-2 restriction of viral egress;ii) characterizing the role of ubiquitin in Vpu-mediated BST-2 degradation;iii) identifying BST-2 binding partners involved in virion tethering or acting as adapters for Vpu function. This progress has allowed us submit a new R01 application """"""""Characterization of Vpu-medicated Degradation of BST-2"""""""". Our BST-2 reagents were also used in collaborative work to examine BST-2 antagonism by the KSHV K5 protein that is now published.
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