Abstract

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. We have also initiated studies aimed at identifying and characterizing host cell factors that interfere with virus release. _____[Corresponds to Freed Project 2 in the October 2011 site visit report of the HIV DRP]

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC010776-09
Application #
9153662
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
9
Fiscal Year
2015
Total Cost
Indirect Cost

  Institution

Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

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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