Innovations in Antiviral Development and the Detection of Virus Infections

227 Pages·1992·16.64 MB·English

by  Bernard N. Fields (auth.)

INNOVATIONS IN
ANTIVIRAL DEVELOPMENT
AND THE DETECTION OF
VIRUS INFECTIONS
ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY
Editorial Board:
NATHAN BACK, State University of New York at Buffalo
IRUN R. COHEN, The Weizmann Institute of Science
DAVID KRITCHEVSKY, Wistar Institute
ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research
RODOLFO PAOLETTI, University of Milan
Recent Volumes in this Series
Volume 309A
PURINE AND PYRIMIDINE METABOLISM IN MAN VII, Part A:
Chemotherapy, ATP Depletion, and Gout
Edited by R. Angus Harkness, Gertrude B. Elion, and Nepomuk Zöllner
Volume 309B
PURINE AND PYRIMIDINE METABOLISM IN MAN VII, Part B:
Structural Biochemistry, Pathogenesis, and Metabolism
Edited by R. Angus Harkness, Gertrude B. Elion, and Nepomuk Zöllner
Volume 310
IMMUNOLOGY OF MILK AND THE NEONATE
Edited by Jiri Mestecky, Claudia Blair, and Pearay L. Ogra
Volume 311
EXCITATION-CONTRACTION COUPLING IN SKELETAL,
CARDIAC, AND SMOOTH MUSCLE
Edited by George B. Frank, C. Paul Bianchi, and Henk E. D. J. ter Keurs
Volume 312
INNOVATIONS IN ANTIVIRAL DEVELOPMENT AND THE DETECTION OF
VIRUS INFECTIONS
Edited by Timothy M. Block, Donald Jungkind, Richard Crowell,
Mark Denison, and Lori R. Walsh
Volume 313
HEPARIN AND RELATED POLYSACCHARIDES
Edited by David A. Lane, Ingemar Björk, and Ulf Lindahl
Volume 314
CELL-CELL INTERACTIONS IN THE RELEASE OF
INFLAMMATORY MEDIATORS: Eicosanoids, Cytokines, and Adhesion
Edited by Patrick Y-K Wong and Charles N. Serhan
Volume 315
TAURINE: Nutritional Value and Mechanisms of Action
Edited by John B. Lombardini, Stephen W. Schaffer, and Junichi Azuma
A Continuation Order Plan is available for this series. A continuation order will bring delivery of each new volume
immediately upon publication. Volumes are billed only upon actual shipment. For further information please contact
the publisher.
INNOVATIONS IN
ANTIVIRAL DEVELOPMENT
AND THE DETECTION OF
VIRUS INFECTIONS
Edited by
Timothy M. Block and
Donald Jimgkind
Thomas Jefferson University Hospital
Philadelphia, Pennsylvania
Richard L. Crowell
Hahnemann University School of Medicine
Philadelphia, Pennsylvania
Mark Denison
Vanderbilt University
Nashville, Tennessee
and
Lori R. Walsh
Mercy Catholic Medical Center
Darby, Pennsylvania
SPRINGER SCIENCE+BUSINESS MEDIA, LLC
Library of Congress Catalog1ng-1n-PublIcatIon Data
Innovations 1n antiviral development and the detection of virus
Infections / edited by Timothy M. Block ... [et al.].
p. cm. — (Advances in experimental medicine and biology ; v.
312)
"Proceedings of the Eastern Pennsylvania Branch of the American
Society for Microbiology Symposium of Innovations 1n Antiviral
Development and the Detection of Virus Infections, held November
15-16, 1990, 1n Philadelphia, Pennsylvania"—T.p. verso.
Includes bibliographical references and Index.
ISBN 978-1-4613-6533-4 ISBN 978-1-4615-3462-4 (eBook)
DOI 10.1007/978-1-4615-3462-4
1. Virus diseases—Molecular aspects—Congresses. 2. Virus
d 1 seases-.-TreatBjent—Congresses. 3. Virus diseases—Dlagnosls-
-Congresses. I. Block, Timothy M. II. American Society for
Microbiology. Eastern Pennsylvania Branch. III. Eastern
Pennsylvania Branch of the American Society for Microbiology
Symposium of Innovations 1n Antiviral Development and the Detection
of Virus Infections (1990 : Philadelphia, Pa.) IV. Series.
[DNLM: 1. Antiviral Agents—congresses. 2. HIV Infectlons-
-prevention & control—congresses. 3. Virus Inhibitors—congresses.
W1 AD559 v. 312 / QV 268.5 158 1990]
RC114.5.152 1992
616.9'25—dc20
DNLM/DLC
for Library of Congress 92-14364
CIP
Proceedings of the Eastern Pennsylvania Branch of the American
Society for Microbiology Symposium of Innovations in Antiviral
Development and the Detection of Virus Infections,
held November 15-16, 1990, in Philadelphia, Pennsylvania
ISBN 978-1-4613-6533-4
© 1992 Springer Science+Business Media New York
Originally published by Plenum Press, New York in 1992
All rights reserved
No part of this book may be reproduced, stored in a retrieval system, or transmitted
in any form or by any means, electronic, mechanical, photocopying, microfilming,
recording, or otherwise, without written permission from the Publisher
Timothy Block dedicates his contributions to his wife, Joan, his
parents, Joyce and Carl, as well as to Russell Schaedler, M.D.
and Baruch Blumberg, M.D., Ph.D. for their inspiration.
Donald Jungkind dedicates his contributions to his patient and
understanding wife, Kim, and to Earle H. Spaulding, Ph.D., who
was influential in his decision to study diagnostic microbiology
and virology.
SYMPOSIUM SPONSORS
AMERICAN CYANAMID COMPANY
BECTON DICKINSON MICROBIOLOGY SYSTEMS
BOEHRINGER INGELHEIM PHARMACEUTICALS, INC.
BOEHRINGER MANHEIM
BURROUGHS WELLCOME
CETUS CORPORATION
DAIICHI PHARMACEUTICAL CORPORATION
ORTHO DIAGNOSITIC SYSTEMS
E. R. SQUIBB PHARMACEUTICAL COMPANY
STERLING DRUG COMPANY
UPJOHN COMPANY
WHITAKER BIOPRODUCTS, INC.
WYETH LABORATORIES, INC.
vii
ACKNOWLEDGEMENTS
The editors wish to thank Margie Pike for her patience and
tireless efforts in the administrative preparation of these
manuscripts. Her influence is evident throughout the book.
We also wish to thank Mary Cohen and Elham Bshouti for
their typing contributions.
viii
FOREWORD
THE ERA OF ANTIVIRALS
Introduction
Although there are more than one hundred medically useful antibiotics and
fungicides, there are only seven compounds licensed for use as antiviral agents, in the
USA. Some of these (acyclovir and ganciclovir) are actually derivatives of each other,
making the number of new discoveries even smaller. Moreover, most of these agents
are of only limited therapeutic value and have substantial toxicity.
It has been more than 100 years ago since Pasteur studied rabies virus (2) and
Rous (4) showed that a small filterable agent (not bacteria) caused disease (sarcoma)
in chickens. It was nearly 100 years ago that yellow fever virus, the first recognized
human pathogenic virus, was unambiguously associated with disease (3). Enteroviruses
were cultured for the first time nearly 50 years ago (1). Why then has effective
chemotherapy against viruses lagged behind that of other microorganisms?
Viruses are often difficult to grow and image. However, with the dynamic
advances in molecular biology and increased sophistication in tissue culture, the field
of virology has blossomed and resulted in improved methods for detection of virus
infection. The use of viruses as models of gene regulation and replication has also
resulted in a massive accumulation of information. The rapid advances in molecular
biology, including the discovery of specific virus functions that differ greatly from the
host and of systems in which virus gene products are expressed, has liberated the study
of some viruses, such as human immunodeficiency virus (HIV) and herpes simplex,
from a dependency upon tissue culture growth. The discovery of virus functions and
replication strategies that differ from their host has made it possible to begin to
specifically target antiviral agents and overcome the main obstacle that designers of
antiviral chemotherapy have faced: to create antiviral agents that block virus
replication but do not substantially interfere with host cell synthetic pathways.
These recent developments give researchers confidence that in the near future
many antiviral agents will be made available for clinical use. Indeed, from a
chemotherapeutic perspective, it is likely that the 1990s may be called the "decade of
antivirals." The meeting that this book is based upon, as well as the proceedings
themselves, are testimony to the prediction that we are reaching a "critical mass" where
the possibility of rapid diagnosis of viral infection plus effective therapy will result in
more widespread demand for these clinical services.
i)(
This publication differs from more conventional reports of virus chemotherapy
in that the authors have been encouraged to be speculative. In addition to the
presentation of data, authors were welcome to make conjecture about experiments that
had not necessarily been conducted and to hypothesize about approaches that have not
yet been taken. We have emphasized innovations because with only a handful of
antiviral agents out there, some new approaches might be helpful.
Highlights of the Book
Some of the highlights of the proceedings are outlined here, although it is noted
that not all of the contributions to this book are considered in this forward.
Antiviral strategists graphically divide the virus life cycle into discreet steps as
outlined below:
Step 0 Processing of the virion in host biological
fluids and access to target tissue
Step I Attachment
Step II Entry and uncoating
Step III Relocation of the viral genome to appropriate
cell compartments for synthetic activity
Step IV Transcription of the viral genome and
translocation of viral mRNA, inhibition of host
macromolecular synthesis or transformation events
Step V Replication
Step VI Assembly and egress
Step VII Immunological effects
x
Although these steps are somewhat artificial, in the sense that the virus life cycle is
actually more of a continuum than a sequence of separately occurring events, they do
help organize our thinking. Indeed, the findings described in this book can, in some
regards, be categorized by the steps that are interfered with. For example, categorizing
certain chapters by the step in the virus life cycle they discuss allows us to offer the
following outline:
Step 0: Processing of the Virus and Access to Host Tissue
The book starts with an important lesson and reminder from Bernard Fields.
Dr Fields emphasizes the limitations of studying viruses in tissue culture and provides
several examples of steps in a virus' life cycle that could only have been revealed by
in vivo analysis of pathogenesis. For example, the proteolytic processing of reovirus
in the mouse gut, a potentially useful target for antiviral action, would not have been
appreciated if analysis of the virus life cycle had been limited to tissue culture.
Dr. Bernard Fields reports that reovirus is proteolytically cleaved in the mouse gut.
This cleavage results in the "activation" of virus attachment proteins, allowing for
efficient binding to the host cell. Inhibition of this processing event results in effective
interference with virus replication in vivo. The dynamics of virus spread throughout
its host are also reviewed. Remarkably, antibody against reovirus administered to mice
that already harbor the virus in their central nervous system can still drastically reduce
the spread of virus throughout specific neurotracts. Other full-length contributions that
deal with an aspect of virus pathogenesis are by Wu et al., and Coen et al.
Step 1: Attachment
Receptors for virus attachment provide very attractive antiviral targets. In
particular, Richard Colonno reviews the use of anti-rhinovirus receptor agents in the
context of the knowledge that the functional receptor is immune cell adhesion
molecule #1. The cellular receptor for HIV has also been targeted. An approach that
targets the virion, rather than the host, is outlined by Berger et al. Briefly, for
example, soluble CD4, the cellular receptor for HIV, has been derivatized and used
to "neutralize" in vitro preparations of the virus. The potential of this agent, in the
context of combination therapy, is presented. Another full-length contribution that
focuses upon virus receptors is by Dutko et al., in which the possibility of using
antiviral agents of known mechanisms of action to probe virus function is discussed.
Step II: EntO' and Uncoating
This step offers opportunities for antiviral action, but is not considered in this
report.
Steps III and IV: Transcription and Replication of the Virus Genome
Included in Steps III and IV are the specific components of the viral
biosynthetic machinery, such as specific enzymes. There are many examples of novel
antivirals in this area. For example, new approaches to the inhibition of the HIV
protease are likely to reach clinical trials shortly. In this book, Merluzzi et aI., report
an exciting novel small organic compound characterized by a cyclic propyl group. This
xi