In most cell types, HIV-1 assembly occurs predominantly on the plasma membrane;however, the itinerary that the Gag precursor follows to reach its destination in the cell and the role that cellular factors play in Gag trafficking remain ill defined. We discovered that a lipid, the phosphoinositide PI(4,5)P2, serves an important function in directing Pr55Gag to the plasma membrane. We are actively engaged in studies that seek to elucidate further the cellular machinery involved in HIV-1 Gag trafficking. This effort builds upon our recent finding that the ADP ribosylation factors (Arfs) and the Golgi-localized, gamma-ear-containing, Arf-binding (GGA) proteins modulate Gag-membrane binding and virus release. Additional Gag partners have recently been identified. These studies, which focus primarily on HIV-1, are also being extended to the nonprimate lentiviruses equine infectious anemia virus (EIAV) and feline immunodeficiency virus (FIV). We recently reported live-cell imaging data demonstrating the movement of HIV-1 Gag to the cell-cell contact site (virological synapse) in infected macrophages;we are currently working to define both viral and cellular determinants that direct Gag to the macrophage synapse. We are also pursuing a long-term interest in the mechanism by which the viral envelope (Env) glycoproteins are incorporated into virus particles. The role of host cell factors in Env incorporation, which remains unresolved and controversial, is being addressed in ongoing studies. [Corresponds to Freed Project 1 in the April 2007 site visit report of the HIV Drug Resistance Program]

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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
Freed, Eric O (2015) HIV-1 assembly, release and maturation. Nat Rev Microbiol 13:484-96
Gerber, Pehuén Pereyra; Cabrini, Mercedes; Jancic, Carolina et al. (2015) Rab27a controls HIV-1 assembly by regulating plasma membrane levels of phosphatidylinositol 4,5-bisphosphate. J Cell Biol 209:435-52
Tedbury, Philip R; Mercredi, Peter Y; Gaines, Christy R et al. (2015) Elucidating the mechanism by which compensatory mutations rescue an HIV-1 matrix mutant defective for gag membrane targeting and envelope glycoprotein incorporation. J Mol Biol 427:1413-1427
Brown, Lola A; Cox, Cassiah; Baptiste, Janae et al. (2015) NMR structure of the myristylated feline immunodeficiency virus matrix protein. Viruses 7:2210-29
Tedbury, Philip R; Freed, Eric O (2015) The cytoplasmic tail of retroviral envelope glycoproteins. Prog Mol Biol Transl Sci 129:253-84
Freed, Eric O; Gale Jr, Michael (2014) Antiviral innate immunity: editorial overview. J Mol Biol 426:1129-32
Daniels, Sarah I; Soule, Erin E; Davidoff, Katharine S et al. (2014) Activation of virus uptake through induction of macropinocytosis with a novel polymerizing peptide. FASEB J 28:106-16
Van Engelenburg, Schuyler B; Shtengel, Gleb; Sengupta, Prabuddha et al. (2014) Distribution of ESCRT machinery at HIV assembly sites reveals virus scaffolding of ESCRT subunits. Science 343:653-6
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

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