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This concept remains the most parsimonious explanation of the evidence to date, and correctly predicted the spread of the BSE agent to vastly divergent species. With the popularization of the prion (infectious protein) hypothesis, substantial data pointing to a TSE virus have been largely ignored. Yet no form of prion protein (PrP) fulfills Koch's postulates for infection. Pathologic PrP is not proportional to, or necessary for infection, and recombinant and \u201camplified\u201d prions have failed to produce significant infectivity. Moreover, the \u201cwealth of data\u201d claimed to support the existence of infectious PrP are increasingly contradicted by experimental observations, and cumbersome speculative notions, such as spontaneous PrP mutations and invisible strain\u2010specific forms of \u201cinfectious PrP\u201d are proposed to explain the incompatible data. The ability of many \u201cslow\u201d viruses to survive harsh environmental conditions and enzymatic assaults, their stealth invasion through protective host\u2010immune defenses, and their ability to hide in the host and persist for many years, all fit nicely with the characteristics of TSE agents. Highly infectious preparations with negligible PrP contain nucleic acids of 1\u20135 kb, even after exhaustive nuclease digestion. Sedimentation as well as electron microscopic data also reveal spherical infectious particles of 25\u201335 nm in diameter. This particle size can accommodate a viral genome of 1\u20134 kb, sufficient to encode a protective nucleocapsid and\/or an enzyme required for its replication. Host PrP acts as a cellular facilitator for infectious particles, and ultimately accrues pathological amyloid features. A most significant advance has been the development of tissue culture models that support the replication of many different strains of agent and can produce high levels of infectivity. These models provide new ways to rapidly identify intrinsic viral and strain\u2010specific molecules so important for diagnosis, prevention, and fundamental understanding. J. Cell. Biochem. 100: 897\u2013915, 2007. \u00a9 2006 Wiley\u2010Liss, Inc.<\/jats:p>","DOI":"10.1002\/jcb.21090","type":"journal-article","created":{"date-parts":[[2006,10,17]],"date-time":"2006-10-17T10:08:52Z","timestamp":1161079732000},"page":"897-915","source":"Crossref","is-referenced-by-count":58,"title":["A 25 nm virion is the likely cause of transmissible spongiform encephalopathies"],"prefix":"10.1002","volume":"100","author":[{"given":"Laura","family":"Manuelidis","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2006,10,16]]},"reference":[{"key":"e_1_2_5_2_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1114168"},{"key":"e_1_2_5_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/39758"},{"key":"e_1_2_5_4_1","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/22.6.1101"},{"key":"e_1_2_5_5_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0400158101"},{"key":"e_1_2_5_6_1","doi-asserted-by":"publisher","DOI":"10.1189\/jlb.72.6.1075"},{"key":"e_1_2_5_7_1","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1172\/JCI200113155","article-title":"Infected splenic dendritic cells are sufficient for prion transmission to the CNS in mouse scrapie","volume":"108","author":"Aucouturier P","year":"2001","journal-title":"J Clin Invest"},{"key":"e_1_2_5_8_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0237313100"},{"key":"e_1_2_5_9_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.76.21.10905-10913.2002"},{"key":"e_1_2_5_10_1","doi-asserted-by":"publisher","DOI":"10.1080\/13550280490261761"},{"key":"e_1_2_5_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/ana.410040303"},{"key":"e_1_2_5_12_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0272-2712(02)00067-7"},{"key":"e_1_2_5_13_1","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.74.12.5542-5547.2000"},{"key":"e_1_2_5_14_1","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0404650101"},{"key":"e_1_2_5_15_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.171.3969.389"},{"key":"e_1_2_5_16_1","doi-asserted-by":"publisher","DOI":"10.1093\/bmb\/66.1.99"},{"key":"e_1_2_5_17_1","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(93)90360-3"},{"key":"e_1_2_5_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2005.02.011"},{"key":"e_1_2_5_19_1","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp.2004.048660"},{"key":"e_1_2_5_20_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.305.5684.589a"},{"key":"e_1_2_5_21_1","doi-asserted-by":"publisher","DOI":"10.3181\/00379727-127-32680"},{"key":"e_1_2_5_22_1","first-page":"63","article-title":"Genetic aspects of unconventional virus infections: The basis of the virino hypothesis","volume":"135","author":"Dickinson AG","year":"1988","journal-title":"Ciba Found Symp"},{"key":"e_1_2_5_23_1","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/117.1.15"},{"key":"e_1_2_5_24_1","doi-asserted-by":"crossref","first-page":"6674","DOI":"10.1128\/jvi.67.11.6674-6681.1993","article-title":"Differential effects of rabies and borna disease viruses on immediate\u2010early\u2010 and late\u2010response gene expression in brain tissues","volume":"67","author":"Fu Z","year":"1993","journal-title":"J Virol"},{"key":"e_1_2_5_25_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.142303"},{"key":"e_1_2_5_26_1","doi-asserted-by":"publisher","DOI":"10.1007\/BF00687377"},{"key":"e_1_2_5_27_1","doi-asserted-by":"publisher","DOI":"10.1093\/emboj\/21.7.1864"},{"key":"e_1_2_5_28_1","doi-asserted-by":"publisher","DOI":"10.1126\/science.1980379"},{"key":"e_1_2_5_29_1","doi-asserted-by":"publisher","DOI":"10.1099\/0022-1317-79-8-2079"},{"key":"e_1_2_5_30_1","doi-asserted-by":"publisher","DOI":"10.1007\/s004010051155"},{"key":"e_1_2_5_31_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.1962"},{"key":"e_1_2_5_32_1","unstructured":"KarolinskaInstitute.1997.Nobel Prize in Medicine.http:\/\/www.nobel.se\/medicine\/laureates\/1997\/presentation\u2010speech.html."},{"key":"e_1_2_5_33_1","doi-asserted-by":"publisher","DOI":"10.1038\/37789"},{"key":"e_1_2_5_34_1","doi-asserted-by":"crossref","first-page":"4142","DOI":"10.1128\/jvi.67.7.4142-4153.1993","article-title":"Interference with superinfection and with cell killing and determination of host range and growth kinetics mediated by feline leukemia virus surface glycoproteins","volume":"67","author":"Kristal B","year":"1993","journal-title":"J Virol"},{"key":"e_1_2_5_35_1","doi-asserted-by":"publisher","DOI":"10.1097\/00005072-197101000-00004"},{"key":"e_1_2_5_36_1","article-title":"Pathological science (transcribed and ed., Robert N. 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