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Archives of Virology Supplement 20 Edited by Charles H. Calisher With advice and contributions by Aleksandr P. Agafonov, M. Javad Aman, Kevin Anderson, Daniel G. Bausch, Sina Bavari, Yevgenii F. Belanov, Matthias Borchert, Joel G. Breman, Alexander A. Bukreyev, Kartik Chandran, Robert Colebunders, Heinz Feldmann, Claude Fauquet, Thomas W. Geisbert, Jean-Paul Gonzalez, Mark Gorwitz, Barry S. Hewlett, David L. Heymann, Frank Hufert, M. Sofi Ibrahim, Tetsuro Ikegami, Peter B. Jahrling, Barbara Johnson, Karl M. Johnson, Alla V. Kachko, Philip J. Kranzusch, Elliot J. Lefkowitz, Eric M. Leroy, Loreen L. Lofts, Shigeru Morikawa, Elke Mühlberger, Frederick A. Murphy, Jean-Jacques Muyembe-Tamfum, Sergei V. Netyosov, Gene G. Olinger, Jr., Sheli R. Radoshitzky, Yurii N. Rassadkin, Yelena I. Ryabchikova, Jean-François Saluzzo, Aleksandr N. Sergeyev, Aleksandr M. Shestopalov, Werner Slenczka, Aleksandr V. Sorokin, Ute Ströher, Ayato Takada, Vladimir A. Ternovoi, Aleksandr S. Vladyko, Viktor Ye. Volchkov, Guido van der Groen, Manfred Weidmann
Jens H. Kuhn Filoviruses A Compendium of 40 Years of Epidemiological, Clinical, and Laboratory Studies
SpringerWienNewYork
Jens H. Kuhn, MD, ScD, MS New England Primate Research Center Harvard Medical School Southborough, MA, USA
This work (book and attached CD-ROM) is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically those of translation, reprinting, re-use of illustrations, broadcasting, reproduction by photocopying machines or similar means, and storage in data banks. Product Liability: The publisher can give no guarantee for all the information contained in this book. This does also refer to information about drug dosage and application thereof. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. # 2008 Springer-Verlag=Wien Printed in Austria SpringerWienNewYork is part of Springer Science þ Business Media springer.at Cover image: Courtesy of Thomas W. Geisbert Typesetting and database programming: Thomson Press (India) Ltd., Chennai Printing: Holzhausen Druck þ Medien, 1140 Wien Printed on acid-free and chlorine-free bleached paper SPIN: 10974742 With 72, partly coloured Figures CIP data applied for
ISSN 0939-1983
ISBN 978-3-211-20670-6 SpringerWienNewYork
Foreword The filoviruses (Lake Victoria marburgvirus and the ebolaviruses) are etiological agents of severe hemorrhagic fevers with extraordinary high casefatality rates for humans, chimpanzees, gorillas, and probably other animals. Natural reservoirs and true geographic distributions of these viruses are unknown. Vaccines for the prevention of filovirus infections and antiviral therapies for the treatment of patients or of infected animals are not yet available. Lake Victoria marburgvirus and ebolavirus research requires maximum-containment laboratory facilities, of which there are only a few worldwide. In the U.S., the filoviruses are classified as Select Agents and National Institute of Allergy and Infectious Diseases (NIAID) Category A Priority Pathogens, and are handled under biosafety-level4 containment to protect laboratory workers from infection and to protect the civilian population. Many institutions and experts consider filoviruses as potential threats to humans because they could be used as biological weapons. This review summarizes in detail the contemporary knowledge of filoviruses and the diseases they cause. The entirety of the open literature on filoviruses, covering all major scientific and clinical fields, is referenced and summarized in this text, including most of the conference abstracts, book chapters, dissertations, government reports, patents, theses, and journal publications in many languages. In total, almost 4,500 references (3,350 citations and 1,150 subcitations, such as abstracts, reprints, or translations) are provided on a CD-ROM as an accompanying reference source for the book – roughly three times the number of references that can be recovered using PubMed searches (1,450).
For ease of retrieval by the reader, all references are cited with original titles in the original spelling, first author names, full journal titles, and issue numbers where possible. The text of this book and the accompanying reference resource will be updated in the future, and thus will provide a robust source of information for filovirologists, other virologists and scientists in general, clinicians, students, journalists, and biodefense professionals. This review is a work in progress. It is expected that it will be expanded, updated, and corrected at regular intervals. To further improve this review, the reader is strongly encouraged to contact the author (fi
[email protected]), editor (
[email protected]), or Springer (fi
[email protected]) to point out errors or to provide missing or ill-cited references, personal thoughts, materials, or observations relevant to filovirology, any or all of which would be most welcome. In a work this large and inclusive, surely many errors remain, for which we apologize. Any errors in this book are the responsibility of the author and editor. Co-editors and reviewers provided guidance. Some assessed particular chapters covering only their areas of expertise, whereas others evaluated the entire manuscript. Occasionally, one reviewer’s point of view contradicted that of another reviewer’s or that of the author and editor. The author and editor decided which suggestions to follow. The views and opinions expressed in this book do not necessarily state or reflect those of the institutions affiliated with the author, editor, or any reviewer or co-editor. Jens H. Kuhn Charles H. Calisher
1 Preface
This review originated from my own need for an extensive review of filovirus (Lake Victoria marburgvirus and ebolavirus) research during my participation in the vaccine-development program at the United States Army Medical Research Institute of Infectious Diseases, Frederick, Maryland from April 1998 to April 1999. I was surprised to discover only specialized articles – a comprehensive work covering all aspects of filovirus research did not exist. Lake Victoria marburgvirus was discovered in 1967 in Germany and Yugoslavia. At the time, it was not unusual for researchers to publish scientific articles in their respective language followed by articles in English. Thus, a large body of literature in non-English languages accumulated, and, to a lesser extent, still accumulates today. In fact, most of the important Soviet and Russian contributions to filovirus research were published in Russian, and many of them have not been indexed or translated, let alone summarized in review articles. I came to realize that most of the non-English publications are not cited in the filovirus literature. One reason for this might be that only a few dedicated researchers would undertake the effort of obtaining and translating these articles. An even more important reason might be that many of the non-English articles are not indexed in the common computerized databases such as PubMed or Ingenta. Many researchers may not be fully aware of all publications, which might lead to redundant research. Another major problem I have encountered is that many references are cited incorrectly or have typographical errors. For example, translations of German articles are often cited when the first emer-
gence of Lake Victoria marburgvirus is described. However, these translations frequently appeared years later than the original publications, or, even worse, are internal translations of specialized institutes and are not easily accessible to the scientific community or the public. Copying of titles in languages other than English with the typical accumulation of typing errors, and the translation of non-English journal titles into English often resulted in almost indecipherable referencing – to the extent that even professional librarians were unable to locate these articles. The bad habit of ‘‘correcting’’ those spelling errors considered to be ‘‘obvious’’ in author lists or titles of journal articles has contributed to the confusion. The widespread interest in filoviruses by the public and the scientific community, and the abovementioned flaws of published articles, stimulated the idea to write this review. Its purpose is to provide an extensive bibliography of filovirus-research publications with emphasis on the African, Dutch, French, German, Japanese, and Russian literature, and to review their contents. Through the references, credit is given to most researchers who, in the past four decades, contributed to today’s knowledge of filoviruses. The references are designed to provide accurate and detailed information to easily locate and retrieve the respective publications. Additional information regarding the articles is also provided, e.g. whether translations of articles are available, whether an article has been published with abstracts in different languages, whether reprints of articles are available, and much more. The full names of researchers are provided if they appeared in a cited publication; the full journal names and the issue
2
numbers of references are provided for easier retrieval by the reader. The collection and analysis of the filovirus research-related documents cited in this review took almost nine years. Often, articles could only be retrieved by contacting individual scientists directly, or by visiting local libraries in many countries. Laboratory rotations at the United States Army Medical Research Institute of Infectious Diseases (1998–1999), at the U.S. Centers for Disease Control and Prevention in Atlanta, Georgia (in 2000), and at the State Research Center for Virology and
Preface
Biotechnology ‘‘Vector’’ in Koltsovo, Novosibirsk Region, Russia (in 2001), allowed me to tap into the knowledge of world-renowned filovirus experts. Many of them reviewed this manuscript and contributed material, personal thoughts, and organizational help. These experts are listed by name in alphabetical order at the beginning of the book. I am eternally grateful for their intellectual input and their enthusiastic support. This review would not have been possible without their help and that of many kind and incredibly patient librarians. Jens H. Kuhn, September 4, 2007
2 Contents
3 LIST OF ABBREVIATIONS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
9
4 INTRODUCTION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.1 Viral hemorrhagic fevers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.2 Filovirus taxonomy, evolution, and phylogeny. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.3 Biosafety concerns in filovirus research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4.4 Biosecurity concerns in filovirus research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
13 19 23 37 50
5 HISTORY OF FILOVIRAL DISEASE OUTBREAKS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1 Lake Victoria marburgvirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.1 Germany and Yugoslavia, 1967, and Uganda, 1967 (speculative) . . . . . . . . . . . . 5.1.2 South Africa, 1973 (speculative) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.3 Rhodesia, 1975 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.4 Kenya, 1980. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.5 Zimbabwe=South Africa, 1982 (speculative). . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.6 Togo, 1985 (speculative) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.7 Kenya, 1987. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.8 Laboratory accident(s), U.S.S.R., 1988 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.9 Kenya=Sweden, 1990 (speculative) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.10 Laboratory accident, U.S.S.R., 1990 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.11 Kenya=Germany, 1993 (speculative) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.12 Zaire, 1987–1996=Democratic Republic of the Congo, 1997–2000 . . . . . . . . . . . 5.1.13 Angola, 2004–2005. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.1.14 Uganda, 2007 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2 Zaire ebolavirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.1 Zaire, 1976 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.2 Zaire, 1977 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.3 Kenya, 1980 (speculative) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.4 Zaire, 1980–1985 (speculative) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.5 Five independent outbreaks, Gabon, 1994–1995 . . . . . . . . . . . . . . . . . . . . . . . . 5.2.6 Zaire, 1995 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.7 Laboratory accident, Russia, 1996. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.8 Gabon, 1996. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.9 Gabon=South Africa, 1996–1997 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.10 Eight independent outbreaks in Gabon and Congo (Brazzaville), 2001–2002 . . . . . 5.2.11 Congo (Brazzaville) and Gabon, 2002 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.12 Three independent outbreaks, Congo (Brazzaville), 2002–2003 . . . . . . . . . . . . . 5.2.13 Congo (Brazzaville), 2003–2004. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
59 64 64 68 68 70 70 70 71 71 71 72 72 73 75 75 75 75 78 79 79 79 80 82 82 82 83 85 85 85
4
Contents
5.3
5.4
5.5
5.6 5.7
5.2.14 Laboratory accident, U.S.A., 2004 (speculative) . . . . . . . . . . . . . . . . . . . . . . . . 5.2.15 Laboratory accident, Russia, 2004. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.2.16 Congo (Brazzaville), 2005 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sudan ebolavirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.1 Sudan, 1976. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.2 Laboratory accident, U.K., 1976 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.3 Sudan, 1979. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.4 Uganda, 2000–2001 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.3.5 Sudan, 2004. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Reston ebolavirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.1 The Philippines=U.S.A., 1989–1990 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.2 The Philippines=Italy, 1992 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.4.3 The Philippines=U.S.A., 1996 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . C^ ote d’Ivoire ebolavirus . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5.5.1 C^ ote d’Ivoire, 1992 (speculative) and C^ote d’Ivoire=Switzerland 1994 . . . . . . . . . 5.5.2 Liberia and C^ ote d’Ivoire, 1995 (speculative) . . . . . . . . . . . . . . . . . . . . . . . . . . . Speculations regarding the occurrence of additional filovirus infections . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
86 86 86 86 86 88 88 88 90 90 90 93 93 94 94 95 95 96
6 CLINICAL PRESENTATION OF FILOVIRAL DISEASE . . . . . . . . . . . . ... . . . . . . . . . . . . 99 6.1 Lake Victoria marburgvirus infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 6.1.1 In humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 99 6.1.2 In nonhuman primates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 104 6.1.3 In guinea pigs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 6.1.4 In other animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 105 6.2 Zaire ebolavirus infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 6.2.1 In humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 106 6.2.2 In nonhuman primates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 110 6.2.3 In guinea pigs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 6.2.4 In mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 113 6.2.5 In other animals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 6.3 Sudan ebolavirus infections. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 6.3.1 In humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 115 6.3.2 In nonhuman primates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 6.3.3 In guinea pigs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 116 6.3.4 In mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 6.4 Reston ebolavirus infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 117 6.5 C^ote d’Ivoire ebolavirus infections . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 6.6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118 7 FILOVIRAL DISEASE PATHOLOGY . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 7.1 Marburgvirus disease pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 7.1.1 In humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 121 7.1.2 In nonhuman primates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 123 7.1.3 In guinea pigs, hamsters, and mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 7.2 Zaire ebolavirus disease pathology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 7.2.1 In humans . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 7.2.2 In nonhuman primates. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 130
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5
7.3 7.4 7.5 7.6
7.2.3 In guinea pigs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136 7.2.4 In mice . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 Sudan ebolavirus disease pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 138 Reston ebolavirus disease pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 139 C^ ote d’Ivoire ebolavirus disease pathology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 140
8 GEOGRAPHIC DISTRIBUTION OF FILOVIRUSES: SEROLOGICAL 8.1 Belarus and Ukraine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.2 Benin. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.3 Botswana . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.4 Burkina Faso . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.5 Cameroon. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.6 Central African Republic . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.7 Congo (Brazzaville). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.8 C^ ote d’Ivoire . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.9 Djibouti . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.10 Ethiopia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.11 Gabon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.12 Guinea . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.13 Kenya . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.14 Liberia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.15 Madagascar. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.16 Nigeria. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.17 Panama . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.18 Philippines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.19 Rhodesia=Zimbabwe . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.20 Senegal . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.21 Sierra Leone . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.22 Sudan. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.23 Togo . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.24 Uganda . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.25 Zaire=Democratic Republic of Congo . . . . . . . . . . . . . . . . . . . . 8.26 Other surveys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8.27 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
SURVEYS . . . . . . . . 143 . . . . . . . . . . . . . . . . . 144 . . . . . . . . . . . . . . . . . 144 . . . . . . . . . . . . . . . . . 144 . . . . . . . . . . . . . . . . . 144 . . . . . . . . . . . . . . . . . 144 . . . . . . . . . . . . . . . . . 145 . . . . . . . . . . . . . . . . . 146 . . . . . . . . . . . . . . . . . 146 . . . . . . . . . . . . . . . . . 146 . . . . . . . . . . . . . . . . . 146 . . . . . . . . . . . . . . . . . 147 . . . . . . . . . . . . . . . . . 147 . . . . . . . . . . . . . . . . . 147 . . . . . . . . . . . . . . . . . 148 . . . . . . . . . . . . . . . . . 148 . . . . . . . . . . . . . . . . . 148 . . . . . . . . . . . . . . . . . 149 . . . . . . . . . . . . . . . . . 149 . . . . . . . . . . . . . . . . . 149 . . . . . . . . . . . . . . . . . 149 . . . . . . . . . . . . . . . . . 149 . . . . . . . . . . . . . . . . . 149 . . . . . . . . . . . . . . . . . 149 . . . . . . . . . . . . . . . . . 150 . . . . . . . . . . . . . . . . . 150 . . . . . . . . . . . . . . . . . 150 . . . . . . . . . . . . . . . . . 151
9 ECOLOGY OF FILOVIRUSES: SEARCH FOR RESERVOIRS . . . . . . . . . . . . . . . . . . . . . . 153 9.1 Filoviruses and their association with nonhuman primates . . . . . . . . . . . . . . . . . . . . . . . 154 9.2 Bats as filovirus reservoirs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 159 9.3 Other possible filovirus reservoirs . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 161 9.4 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 169 10 CULTIVATION OF FILOVIRUSES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 10.1 Lake Victoria marburgvirus in cell cultures. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 171 10.2 Ebolaviruses in cell cultures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 172 11 MOLECULAR CHARACTERISTICS OF FILOVIRUSES . . . . . . . . . . . . . . . . . . . . . . . . . . 175 11.1 Ultrastructure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 11.2 Filoviral genomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 179
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11.3 Filoviral subgenomic mRNAs and their expression products . . . . . . . . . . . . . . . . . . . . . . 190 11.3.1 The nucleoprotein gene (NP) and its expression product (nucleoprotein, NP). . . . . . .191 11.3.2 The VP35 gene and its expression product (viral protein 35, VP35) . . . . . . . . . . 200 11.3.3 The VP40 gene and its expression product (matrix protein, VP40) . . . . . . . . . . 201 11.3.4 The ebolavirus GP gene and its primary expression product (secreted glycoprotein, sGP) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 205 11.3.5 The ebolaviral GP gene and its secondary expression product (spike protein, GP1,2) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 208 11.3.6 The ebolaviral GP gene and its tertiary expression product (secondary secreted glycoprotein, ssGP). . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 215 11.3.7 The marburgviral GP gene and its expression product (spike protein, GP1,2) . . . . . . 216 11.3.8 The VP30 gene and its expression product (VP30) . . . . . . . . . . . . . . . . . . . . . . 219 11.3.9 The VP24 gene and its expression product (VP24) . . . . . . . . . . . . . . . . . . . . . . 221 11.3.10 The L gene and its expression product (RNA-dependent RNA polymerase, L). . . . . 222 11.4 Cellular filovirus lifecycle. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 225 11.4.1 Filovirus cell entry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 11.4.2 Transcription of filoviral genomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 241 11.4.3 Replication of filoviruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 11.4.4 Filovirus maturation and egress. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 244 11.5 Pathogenesis of filoviral disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 251 11.6 Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 263 12 LABORATORY DIAGNOSIS OF FILOVIRAL DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . 265 12.1 Detection of filoviral RNA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 268 12.2 Filovirus isolation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 12.3 Detection of filoviral antigen. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 12.3.1 Immunofluorescent assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 271 12.3.2 Antigen-capture ELISA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273 12.3.3 Other assays for filoviral antigen detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 12.4 Detection of specific antibodies to filoviruses . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 12.4.1 Immunofluorescent assays . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 12.4.2 IgM-capture ELISA and IgG ELISA . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 274 12.4.3 Other assays for antibody detection . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 275 12.4.4 Recombinant filoviral antigens for antibody-detection assays . . . . . . . . . . . . . . . 276 12.5 Immunohistochemistry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 12.6 Electron microscopy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 276 12.7 Outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 277 13 OUTBREAK CONTAINMENT . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 13.1 Global containment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 279 13.2 Outbreak control in Africa . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 282 13.3 Outbreak control in developed countries. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 293 14 INACTIVATION OF FILOVIRUSES AND DISINFECTION PROTOCOLS . . . . . . . . . . . . . . 297 15 VACCINE DEVELOPMENT. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 301 15.1 Inactivated filovirions and filovirus-like particles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 304 15.2 DNA candidate vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 313 15.3 Adenovirus candidate vaccines . . . . . . . . . . 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15.4 15.5 15.6 15.7 15.8 15.9 15.10 15.11 15.12
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Venezuelan equine encephalitis virus-based candidate vaccines Vaccinia virus-based candidate vaccines . . . . . . . . . . . . . . . . Picornavirus-based candidate vaccines . . . . . . . . . . . . . . . . . Vesiculovirus-based candidate vaccines. . . . . . . . . . . . . . . . . Respirovirus-based candidate vaccines . . . . . . . . . . . . . . . . . Subunit candidate vaccines . . . . . . . . . . . . . . . . . . . . . . . . . Attenuated candidate vaccines . . . . . . . . . . . . . . . . . . . . . . . Other candidate vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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16 TREATMENT OF FILOVIRAL DISEASE . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335 16.1 Supportive treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 335 16.2 Mitigating filoviral disease by modifying host responses. . . . . . . . . . . . . . . . . . . . . . . . . 336 16.2.1 Administration of interferon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336 16.2.2 Modifying cytokine responses. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 336 16.2.3 Modulation of coagulation disturbances . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337 16.2.4 Traditional treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 337 16.2.5 Homeopathic approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338 16.3 Filovirus-specific antivirals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338 16.3.1 Prevention of filovirus cell entry . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 338 16.3.2 Terpenes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342 16.3.3 Nucleosides . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 342 16.3.4 Antisense approaches. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 343 16.3.5 Other approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 16.4 Combinatorial treatment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 345 17 APPENDIX: Members of the Filoviridae Study Group, ICTV. . . . . . . . . . . . . . . . . . . . . . . . 347 18 LIST OF CONTRIBUTORS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 349 19 ACKNOWLEDGMENTS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 357 20 NOTES ABOUT REFERENCES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 359 21 INDEX . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 361 22 NOTES ABOUT CD-ROM USE . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . . . . . . . . 413
3 List of abbreviations Frequently used abbreviations are in bold. aa AAHL AcMNPV ADAM AFENET AFHF AHF AIDS ALP AMRV BHK BNI -Bon BSC BSL c3-Npc A CaMKII CAMR Cat CAT CBHF C-c3Ado CCHFV CCID CCMB CD CDC CeHV-1 cIAP CIDRAP CIEBOV CIP CIRMF
amino acid(s) Australian Animal Health Laboratory Autographa californica multiple nucleopolyhedrovirus a disintegrin and metalloprotease African Field Epidemiology Network African filoviral hemorrhagic fever Argentinian hemorrhagic fever= ‘African hemorrhagic fever’ acquired immunodeficiency syndrome alkaline phosphatase Amur virus baby hamster kidney Bernhard-Nocht-Institut f€ ur Tropenmedizin Boniface (isolate) biological safety cabinet biosafety level 3-deazaneplanocin A calmodulin-dependent protein kinase II Centre for Applied Microbiological Research cathepsin gene chloramphenicol acetyl transferase ‘cercopithecus-borne hemorrhagic fever’ carbocyclic 3-deazaadenosine= 3-deazaaristeromycin Crimean-Congo hemorrhagic fever virus Coordinating Center for Infectious Diseases Centre for Cellular and Molecular Biology cluster of differentiation Centers for Disease Control (and Prevention) cercopithecine herpesvirus 1 cellular-inhibitor-of-apoptosis protein Center for Infectious Disease Research & Policy Coˆte d’Ivoire ebolavirus calf-intestinal alkaline phosphatase Centre International du Recherches Medical de Franceville
CISA CKII CL CMH CNS CPE CPHL -Cru CSIRO CTL CV-N DBSV DCLS DC-SIGN DC-SIGNR DENV DHS DIC DOBV DRC DRM dstl DTIC DVRD EBOV EC50 ECOFAC
EGTA EHF ELF ELISA ENIVD ERK
Centro de Investigaci on en Sanidad Animal casein kinase II (CKII) containment level cynomolgus macaque heart central nervous system cytopathic effect(s) Central Public Health Laboratory Cruickshank (isolate) Commonwealth Scientific and Industrial Research Organization cytotoxic T-cell cyanovirin-N Da Bie Shan virus Division of Consolidated Laboratory Services dendritic cell-specific ICAM-3-grabbing non-integrin DC-SIGN-Related Dengue virus Department of Homeland Security disseminated intravascular coagulation Dobrava-Belgrade virus Democratic Republic of the Congo detergent-resistant membrane fraction Defence Science and Technology Laboratory Defense Technical Information Center Division of Viral and Rickettsial Diseases ‘Ebola virus’ 50% maximum-effective concentration Conservation et utilisation rationelle des ECOsystemes Forestiers d’Afrique Centrale ethylene glycol tetraacetic acid ‘‘Ebola hemorrhagic fever’’ embryonic lung fibroblasts enzyme-linked immunosorbent assay European Network for Diagnostics of ‘‘Imported’’ Viral Diseases extracellular signal-regulated kinase
10 ESCRT EVD EWARN FACS FADD FAS FasL FDP FIV FMS FOMETRO fVLP -Gab GAHMU GFP GGT GM1 GM-CSF GOARN GP GP GPI GTOV GTR -Gul HA HE HEK HEPA HeV HFRS HHS HIV hMGL
HMVEC HOKV HOS HPIV HPIV-3 HPLC HSADL HTNV HUVE i.m. i.p. i.v. IC50 ICAM
List of abbreviations endosome-associated complex required for transport ‘Ebola virus disease’ Early Warning Alert and Response Network fluorescence-activated cell sorting Fas-associated death-domain protein Federation of American Scientists Fas ligand fibrin degradation product(s) feline immunodeficiency virus ‘Frankfurt-Marburg syndrome’ Belgian Fonds Medical Tropical filovirus-like particle(s) Gabon (isolate) Great Ape Health Monitoring Unit green fluorescent protein g-glutamyl transpeptidase monosialotetrahexosylganglioside granulocyte-macrophage colonystimulating factor Global Outbreak Alert and Response Network glycoprotein glycoprotein gene glycosyl-phosphatidyl-inositol Guanarito virus general time reversible Gulu (isolate) hemagglutinin hematoxylin-eosin human embryonic kidney high-efficiency particulate-absorbing Hendra virus hemorrhagic fever with renal syndrome (Department of) Health and Human Services human immunodeficiency virus human macrophage galactose- and N-acetylgalactosamine-specific C-type lectin human lung-derived microvascular endothelial cell(s) Hokkaido virus human osteosarcoma human parainfluenza virus human parainfluenza virus 3 high-performance liquid chromatography High-Security Animal Disease Laboratory Hantaan virus human umbilical vein endothelial intramuscular(ly) intraperitoneal(ly) intravenous(ly) 50% maximum-inhibitory concentration intercellular adhesion molecule
ICD ICTV IEM IFA IFN IL ILEV INIA INMI INSERM IRF ISTC IVI JUNV KCB KEMRI KFDV -Kik L L l L-SIGN LASV LD50 LNA LPS M M mAb mAbs MACV -Mal MAP MAPK MARV -May MBGV MBL MBP MCL MCP MDCK MELAS MHC MLD MLV
International Statistical Classification of Diseases and Related Health Problems International Committee on Taxonomy of Viruses immunoelectron microscopy indirect immunofluorescent assay interferon interleukin Ilesha virus Instituto Nacional de Investigaci on y Tecnologı´a Agraria y Alimentaria Istituto Nazionale per le Malattie Infettive Lazzaro Spallanzani Institut National de la Sante et de la Recherche Medicale IFN-regulatory factor International Science and Technology Center Institut f€ ur Viruskrankheiten und Immunprophylaxe Junı´n virus Kunskapscentrum f€ or Mikrobiologisk Beredskap Kenya Medical Research Institute Kyasanur Forest disease virus Kikwit (isolate) RNA-dependent RNA polymerase RNA-dependent RNA polymerase gene leader sequence liver=lymph node-specific ICAM-3-grabbing non-integrin Lassa virus median lethal dose locked nucleic acid(s) lipopolysaccharide matrix protein matrix-protein gene monoclonal antibody monoclonal antibodies Machupo virus Maleo (isolate) mitogen-activated protein mitogen-activated protein kinase Lake Victoria marburgvirus Mayinga (isolate) ‘Marburg virus’ Maximum Biosafety Level mannose-binding protein Maximum-containment Level macrophage chemotactic protein Madin-Darby canine kidney mitochondrial encephalopathy with lactic acidemia and stroke-like episodes major histocompatibility complex mucin-like domain murine leukemia virus
List of abbreviations MoMLV MUJV MVD mVLP N N NAIP NASA NBACC NBAF NCZVED NHSQL NIAID NIBSC NICD NIH NIMR NIS NIV NiV NK NNS NP NP NPC-1 NRIV NSB OHFV OKIMO ORF ORSTOM -Ozo PAPR PC PCR pfu -Phi PIADC PKR PMO PNA POD -Pop pp PRNT PT PTAH
Moloney murine leukemia virus Muju virus marburgvirus disease MARV-like particles nucleocapsid protein nucleocapsid protein gene neuronal apoptosis-inhibitory protein National Aeronautics and Space Administration National Biodefense Analysis and Countermeasures Center National Bio- and Agro-Defense Facility National Center for Zoonotic, VectorBorne, and Enteric Diseases National High Security Quarantine Laboratory National Institute of Allergy and Infectious Diseases National Institute for Biological Standards and Control National Institute for Communicable Diseases National Institutes of Health National Institute for Medical Research Newly Independent States National Institute of Virology Nipah virus natural killer nonsegmented negative-stranded nucleoprotein nucleoprotein gene Niemann Pick C-1 Ngari virus Niveau de Securite Biologique Omsk hemorrhagic fever virus Offices de Mines d’Or de Kilo Mito open reading frame Office de la Recherche Scientifique et Technique d’Outre-Mer Ozolin (isolate) powered air-purifying respirator(s) physical containment polymerase-chain reaction plaque-forming unit(s) Philippines1989 (isolate) Plum Island Animal Disease Center dsRNA-dependent protein kinase phosphorodiamidate morpholino oligomer(s) peptide nucleic acid horseradish peroxidase Poppinga (isolate) plaque pick plaque-reduction neutralization test prothrombin time Mallory’s phosphotungstic acid-hematoxilin
11 PTT PUUV -Rat RBD REBOV -Res RIA RIG-I RIKEN RIP rNAPc2 RISC RNAi RNP R.S.F.S.R. RSPCA RSS RT-LAMP RT-PCR RVFV s.c. SAAV SABV scFv SCID SDS SEBOV SEIR SEOV SEVD SFBR SGOT sGP SGPT -Sie siRNA SIV SMI SNALP SNOPB SPA SPB SRCVB SRIEM ssGP S.S.R.
partial thromboplastin time Puumala virus Ratayczak (isolate) receptor-binding domain Reston ebolavirus Reston (isolate) radioimmunoassay retinoic acid-inducible gene I Institute of Physical and Chemical Research receptor-interacting protein recombinant nematode anticoagulant protein c2 RNA-induced silencing complex RNA interference ribonucleoprotein (complex) Russian Soviet Federative Socialist Republic Royal Society for the Prevention of Cruelty to Animals RNA-silencing suppressor reverse-transcription loop-mediated isothermal amplification reverse-transcription PCR Rift Valley fever virus subcutaneous(ly) Saaremaa virus Sabia´ virus single chain variable fragment(s) severe combined immunodeficiency sodium dodecyl sulfate Sudan ebolavirus susceptible-exposed-infectious-recovered Seoul virus Sudan ebolavirus disease Southwest Foundation for Biomedical Research serum glutamic-oxaloacetic transaminase secreted=soluble glycoprotein serum glutamic-pyruvic transaminase Siena (isolate) short double-stranded interfering RNA simian immunodeficiency virus Smittskyddsinstitutet stable nucleic-acid-lipid particle Stepnogorsk Scientific ExperimentalIndustrial Base Scientific-Production Association Special Pathogens Branch State Research Center for Virology and Biotechnology Scientific-Research Institute for Epidemiology and Microbiology secondary secreted==soluble glycoprotein Soviet Socialist Republic
12 STAT SU t TACE -Tan TBEV-FE TCID50 -Tex TM TNF-a TRAIL TREM Tsg TsSDL
UEV UNESP UNICEF USAMRIID USDA UTMB UV UVRI
List of abbreviations signal transducer and activator of transcription surface (unit) trailer sequence TNF-a-converting enzyme Tandala (isolate) tick-borne encephalitis virus, Far Eastern subtype 50% tissue-culture infective dose Texas (isolate) transmembrane (unit) tumor necrosis factor a TNF-related apoptosis-inducing ligand triggering receptors expressed in myeloid cells tumor-susceptibility gene Center of Special Laboratory Diagnostics and Treatment of Especially Dangerous and Exotic Infectious Diseases ubiquitin-conjugating E2-enzyme-variant Universidade Estadual Paulista ‘‘J ulio de Mesquita Filho’’ United Nations Children’s Fund U.S. Army Medical Research Institute of Infectious Diseases U.S. Department of Agriculture University of Texas Medical Branch ultraviolet Uganda Virus Research Institute
VARV VEEV VHF VIDRL -Voe VP VP VSIV WESSV WHO WNV YFV -Zai ZAP ZEBOV ZEVD zeVLP ’=O%# =33]; =A? E=?A# OE)9
Variola virus Venezuelan equine encephalitis virus viral hemorrhagic fever Victorian Infectious Disease Reference Laboratory Voege (isolate) viral protein viral protein gene vesicular stomatitis Indiana virus Wesselsbron virus World Health Organization West Nile virus yellow fever virus Zaire (isolate) zinc finger antiviral protein Zaire ebolavirus Zaire ebolavirus disease ZEBOV-like particles ’@cy*apcH&e>>Z6 =ayR>Z6 Oe>Hp %4pyc@:@(44 4 #4@Hex>@:@(44 =ayR>@-3cc:e*@&aHe:\ck46 3>cH4HyH ]B4*e@-Ap@42&@*cH&e>>@e ?bpe*4>e>4e EHeB>@(@pckab =ayR>ab ?BZH>@Ap@>ab #a2a Oe>Hp EBeP4a:\>@6 9ab@paH@p>@6 )4a(>@cH4k4 4 94Re>4b ?c@b@ ?Bac>Zx 4 ]k2@H4Reck4x 3>LekP4@>>Zx 1ab@:e&a>46
