The release of retrovirus particles from the infected cell is greatly stimulated by late domains present within the Gag precursor protein. We played a key early role in this field by identifying the PTAP late domain of HIV-1, and subsequent studies from our lab and others demonstrated that late domains function by interacting with components of the endosomal sorting (ESCRT) machinery. We continue to be actively involved in elucidating the host cell machinery involved in the release of HIV-1 and other lentiviruses (e.g., EIAV and FIV) and have initiated a high-throughput screen with the NIH Chemical Genomics Center to identify small-molecule inhibitors of HIV-1 budding. We have also initiated studies aimed at defining the mechanism by which the recently discovered host restriction factor CD317 (tetherin) blocks HIV-1 release and the process by which the viral protein Vpu counteracts this restriction. [Corresponds to Freed Project 2 in the April 2007 site visit report of the HIV Drug Resistance Program]

National Institute of Health (NIH)
National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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Tedbury, Philip R; Freed, Eric O (2015) HIV-1 gag: an emerging target for antiretroviral therapy. Curr Top Microbiol Immunol 389:171-201
Park, Sang Yoon; Waheed, Abdul A; Zhang, Zai-Rong et al. (2014) HIV-1 Vpu accessory protein induces caspase-mediated cleavage of IRF3 transcription factor. J Biol Chem 289:35102-10
Waheed, Abdul A; Kuruppu, Nishani D; Felton, Kathryn L et al. (2014) In COS cells Vpu can both stabilize tetherin expression and counteract its antiviral activity. PLoS One 9:e111628
Bird, Sara W; Kirkegaard, Karla; Agbandje-McKenna, Mavis et al. (2014) The ins and outs of viral infection: keystone meeting review. Viruses 6:3652-62
Luttge, Benjamin G; Panchal, Prashant; Puri, Vinita et al. (2014) Mutations in the feline immunodeficiency virus envelope glycoprotein confer resistance to a dominant-negative fragment of Tsg101 by enhancing infectivity and cell-to-cell virus transmission. Biochim Biophys Acta 1838:1143-52
Li, Minghua; Ablan, Sherimay D; Miao, Chunhui et al. (2014) TIM-family proteins inhibit HIV-1 release. Proc Natl Acad Sci U S A 111:E3699-707
Keren-Kaplan, Tal; Attali, Ilan; Estrin, Michael et al. (2013) Structure-based in silico identification of ubiquitin-binding domains provides insights into the ALIX-V:ubiquitin complex and retrovirus budding. EMBO J 32:538-51
Waheed, Abdul A; Freed, Eric O (2012) HIV type 1 Gag as a target for antiviral therapy. AIDS Res Hum Retroviruses 28:54-75
Kuo, Lillian; Freed, Eric O (2012) ARRDC1 as a mediator of microvesicle budding. Proc Natl Acad Sci U S A 109:4025-6
Kim, Sung-Eun; Liu, Fa; Im, Young Jun et al. (2011) Elucidation of New Binding Interactions with the Tumor Susceptibility Gene 101 (Tsg101) Protein Using Modified HIV-1 Gag-p6 Derived Peptide Ligands. ACS Med Chem Lett 2:337-341

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