The biology and evolution of retroviruses and eukaryotic cells is very closely linked. In general, our research seeks to define how the replication of retroviruses is influenced by host gene products, with an emphasis on human and primate immunodeficiency viruses. We work in a variety of areas, but the two major themes are: (1) the identification and characterization of host-cell factors and pathways that are mimicked, manipulated and/or exploited by retroviruses and (2) identifying and understanding the mechanistic basis of host functions that have evolved specifically to provide a defense against retrovirus infection.

How the virion components Gag, Pol, Env, and RNA are transported, assembled and released from cells as infectious particles is one major focus of our efforts. The precise role of host and viral proteins in these processes has been one of the most challenging areas in retrovirology, but is gradually becoming understood. For example, we and others have shown that essentially all retroviruses, and many other enveloped viruses specifically recruit class E VPS proteins and ubiquitin ligases that normally mediate the sorting of cellular cargo at the limiting membrane of endosomes and the budding of vesicles into the endosomal lumen. Indeed, viral proteins appear able to simply redirect required cellular machinery to a different location in the cell in order to facilitate the formation of an enveloped virus particle. Other problems that we are investigating include defining how retroviral proteins select the locations within the cell at which they are assembled - in particular how this is affected by the cytoskeleton, vesicular transport pathways and the intrinsic membrane binding and multimerizing properties of Gag proteins.

Our second major area of interest is "intrinsic immunity." Throughout their evolution, most eukaryotic organisms have frequently been colononized by retrovirus. Indeed, our own genome contains a fossil record of vast numbers of now extinct retroviruses that replicated in the ancestors of modern humans, stretching back over millions of years. Because this historical barrage of retroviral infections, evolution has equipped mammals with several gene products whose primary function is to prevent or attenuate retrovirus replication. We work on several types of inhibitors that attenuate retrovirus replication: one class (exemplified by Fv1 and TRIM5) blocks infection by targeting incoming retrovirus capsids, a second comprises cytidine deaminases (eg. APOBEC3G) that induce lethal hypermutation of retroviral genomes, while a third (as yet poorly understood) activity appears to prevent the release of retroviruses from infected cells. We are also working to discover new types of natural antiretroviral defenses. Understanding how these defenses work, how ancient retroviruses may have been extinguished by them and how some retroviruses have acquired new functions that confer resistance to natural defenses could provide new opportunities to develop improved animal models of AIDS, as well as new therapies.

                  Hatziioannou T, Martin-Serrano J, Zang T and Bieniasz PD. 2005. Matrix-induced inhibition of membrane binding contributes to human immunodeficiency virus type 1 particle assembly defects in murine cells. J Virol. 79:15586-15589. [view]

                  Bieniasz PD. 2006. Late budding domains and host proteins in enveloped virus release. Virology 344:55-63. [view]

                  Zennou V and Bieniasz PD. 2006. Comparative analysis of the antiretroviral activity of APOBEC3G and APOBEC3F from primates. Virology 349:31-40. [view]

                  Neil SJ, Eastman SW, Jouvenet N, Bieniasz PD. 2006. HIV-1 Vpu promotes release and prevents endocytosis of nascent retrovirus particles from the plasma membrane. PLoS Pathog. 2006 May;2(5):e39 [view]

                  Lloyd AG, Tateishi S, Bieniasz PD, Muesing MA, Yamaizumi M, Mulder LC. 2006. Effect of DNA repair protein Rad18 on viral infection. PLoS Pathog. 2(5):e40. [view]

                  Zhang F, Hatziioannou T, Perez-Caballero D, Derse D, Bieniasz PD. 2006. Antiretroviral potential of human tripartite motif-5 and related proteins. Virology. 30;353(2):396-409. [view]

                  Hatziioannou T, Princiotta M, Piatak M Jr, Yuan F, Zhang F, Lifson JD, Bieniasz PD. 2006. Generation of simian-tropic HIV-1 by restriction factor evasion. Science. 314(5796):95. [view]

                  Jouvenet N, Neil SJ, Bess C, Johnson MC, Virgen CA, Simon SM, Bieniasz PD. 2006. Plasma membrane is the site of productive HIV-1 particle assembly. PLoS Biol. 4(12):e435. [view]

                  Lee YN, Bieniasz PD. 2007. Reconstitution of an infectious human endogenous retrovirus. PLoS Pathog. 3(1):e10. [view]

                  Bieniasz PD. 2007. An intrinsic host defense against HIV-1 integration? J Clin Invest. 117(2):302-4. [view]

                  Evans MJ, von Hahn T, Tscherne DM, Syder AJ, Panis M, Wölk B, Hatziioannou T, McKeating JA, Bieniasz PD, Rice CM. 2007. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature. 2007 Apr 12;446(7137):1 p following 805. [view]

                  Ambrose Z, KewalRamani VN, Bieniasz PD, Hatziioannou T. 2007. HIV/AIDS: in search of an animal model. Trends Biotechnol. 25(8):333-7. [view]

                  Neil SJ, Sandrin V, Sundquist WI, Bieniasz PD. 2007. An interferon-alpha-induced tethering mechanism inhibits HIV-1 and Ebola virus particle release but is counteracted by the HIV-1 Vpu protein. Cell Host Microbe. 2007 Sep 13;2(3):193-203. [view]

                  Zhadina M, McClure MO, Johnson MC, Bieniasz PD. 2007. Ubiquitin-dependent virus particle budding without viral protein ubiquitination. Proc Natl Acad Sci. 104(50):20031-6. [view]

                  Neil SJ, Zang T, Bieniasz PD. 2008. Tetherin inhibits retrovirus release and is antagonized by HIV-1 Vpu. Nature. 451(7177):425-30. [view]

                  Virgen CA, Kratovac Z, Bieniasz PD, Hatziioannou T. 2008. Independent genesis of chimeric TRIM5-cyclophilin proteins in two primate species. Proc Natl Acad Sci. 105(9):3563-8.[view]

                  Zhang F, Perez-Caballero D, Hatziioannou T, Bieniasz PD. 2008. No effect of endogenous TRIM5alpha on HIV-1 production. Nat Med. 14(3):235-6. [view]

                  Kratovac Z, Virgen CA, Bibollet-Ruche F, Hahn BH, Bieniasz PD, Hatziioannou T. 2008. Primate lentivirus capsid sensitivity to TRIM5 proteins. J Virol. 82(13):6772-7. [view]

                  Ho DD, Bieniasz PD. 2008. HIV-1 at 25.Cell. 133(4):561-5. [view]

                  Jouvenet N, Bieniasz PD, Simon SM. 2008. Imaging the biogenesis of individual HIV-1 virions in live cells. Nature. 454(7201):236-40. [view]

                  Lee YN, Malim MH, Bieniasz PD. 2008. Hypermutation of an ancient human retrovirus by APOBEC3G. J Virol. 2008 Sep;82(17):8762-70. [view]

                  Perez-Caballero D, Soll SJ, Bieniasz PD. 2008. Evidence for restriction of ancient primate gammaretroviruses by APOBEC3 but not TRIM5alpha proteins. PLoS Pathog. 2008 Oct;4(10):e1000181. [view]

                  Jouvenet N, Neil SJ, Zhadina M, Zang T, Kratovac Z, Lee Y, McNatt M, Hatziioannou T, Bieniasz PD. 2009. Broad-spectrum inhibition of retroviral and filoviral particle release by tetherin. J Virol. 83(4):1837-44. [view]

                  McNatt MW, Zang T, Hatziioannou T, Bartlett M, Fofana IB, Johnson WE, Neil SJ, Bieniasz PD. 2009. Species-specific activity of HIV-1 Vpu and positive selection of tetherin transmembrane domain variants. PLoS Pathog. 5(2):e1000300. [view]

                  Hatziioannou T, Ambrose Z, Chung NP, Piatak M Jr, Yuan F, Trubey CM, Coalter V, Kiser R, Schneider D, Smedley J, Pung R, Gathuka M, Estes JD, Veazey RS, KewalRamani VN, Lifson JD, Bieniasz PD. 2009. A macaque model of HIV-1 infection. Proc Natl Acad Sci. 106(11):4425-9. [view]

                  Brady T, Lee YN, Ronen K, Malani N, Berry CC, Bieniasz PD, Bushman FD. 2009. Integration target site selection by a resurrected human endogenous retrovirus. Genes Dev. 23(5):633-42. [view]

                  Eastman SW, Yassaee M, Bieniasz PD. 2009. A role for ubiquitin ligases and Spartin/SPG20 in lipid droplet turnover. J Cell Biol. 184(6):881-94. [view]

                  Zhang F, Wilson SJ, Landford WC, Virgen B, Gregory D, Johnson MC, Munch J, Kirchhoff F, Bieniasz PD, Hatziioannou T. 2009. Nef proteins from simian immunodeficiency viruses are tetherin antagonists. Cell Host Microbe. 6(1):54-67. [view]

                  Bieniasz PD. 2009. The cell biology of HIV-1 virion genesis. 5(6):550-8. Review. [view]

                  Neil S, Bieniasz P. 2009. Human immunodeficiency virus, restriction factors, and interferon. 29(9):569-80. Review. [view]

                  Jouvenet N, Simon SM, Bieniasz PD. 2009. Imaging the interaction of HIV-1 genomes and Gag during assembly of individual viral particles. Proc Natl Acad Sci U S A. 106(45):19114-9. [view]

                  Perez-Caballero D, Zang T, Ebrahimi A, McNatt MW, Gregory DA, Johnson MC, Bieniasz PD. 2009. Tetherin inhibits HIV-1 release by directly tethering virions to cells. Cell. 2009 Oct 30;139(3):499-511. [view]

                  Sauter D, Schindler M, Specht A, Landford WN, Münch J, Kim KA, Votteler J, Schubert U, Bibollet-Ruche F, Keele BF, Takehisa J, Ogando Y, Ochsenbauer C, Kappes JC, Ayouba A, Peeters M, Learn GH, Shaw G, Sharp PM, Bieniasz P, Hahn BH, Hatziioannou, T, Kirchhoff F. 2009. Tetherin-driven adaptation of Vpu and Nef function and the evolution of pandemic and nonpandemic HIV-1 strains. Cell Host Microbe. 6(5):409-21. [view]

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