The release of retrovirus particles from the infected cell is greatly stimulated by "late" domains present within the Gag precursor protein. Three distinct retroviral late-domain sequences have been identified: Pro-Thr/Ser-Ala-Pro (PTAP or PSAP), Pro-Pro-X-Tyr (PPXY, where X is any amino acid), and Tyr-Pro-Xn-Leu (YPXnL). We played a key early role in identifying the PTAP late domain of HIV-1, and, along with other labs, contributed to the discovery that late domains function by interacting with components of the endosomal sorting complex required for transport (ESCRT) machinery. We continue to be actively involved in elucidating the host cell machinery required for the release of HIV-1 and other lentiviruses (e.g., EIAV and FIV) and are in the process of identifying inhibitors of retrovirus budding. Much of our recent effort in this area is focused on the role of Alix in HIV-1 budding and cell-cell transfer. [Corresponds to Freed Project 2 in the October 2011 site visit report of the HIV Drug Resistance Program]

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National Cancer Institute (NCI)
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National Cancer Institute Division of Basic Sciences
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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
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
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
Adamson, Catherine S; Freed, Eric O (2009) Anti-HIV-1 therapeutics: from FDA-approved drugs to hypothetical future targets. Mol Interv 9:70-4
Waheed, Abdul A; Ono, Akira; Freed, Eric O (2009) Methods for the study of HIV-1 assembly. Methods Mol Biol 485:163-84
Adamson, Catherine S; Freed, Eric O (2008) Recent progress in antiretrovirals--lessons from resistance. Drug Discov Today 13:424-32
Joshi, Anjali; Garg, Himanshu; Nagashima, Kunio et al. (2008) GGA and Arf proteins modulate retrovirus assembly and release. Mol Cell 30:227-38
Waheed, Abdul A; Freed, Eric O (2008) Peptide inhibitors of HIV-1 egress. ACS Chem Biol 3:745-7