Table Of ContentCurrent Topics in
Microbiology
134 and Immunology
Editors
A Clarke, Parkvi11eNictoria . R W. Compans,
Binningham/A labama . M Cooper, Birmingham!A labama
H. Eisen, Paris . W. Goebel, Wfuzburg . H. Koprowski,
Philadelphia . F. Melchers, Basel . M Oldstone,
La Jolla/California . P.K Vogt, Los Angeles
H. Wagner, Ulm . 1. Wilson, La Jolla/California
This collection of studies was conceived as part of a two
volume review of the subject. The contents of Volume 133
are listed below.
Arenaviruses: Genes, Proteins, and Expression
M.B.A. OLDSTONE: The Arenaviruses - An Introduction
D.H.L. BISHOP and D.D. AUPERIN: Arenavirus Gene Struc-
ture and Organization
P.l. SOUTHERN and D.H.L. BISHOP: Sequence Comparison
Among Arenaviruses
M.l. BUCHMEIER and B.S. PAREKH: Protein Structure and
Expression Among Arenaviruses
Y. RIVIERE: Mapping Arenavirus Genes Causing Virulence
S.l. FRANCIS, P.l. SOUTHERN, A. VALSAMAKIS, and M.B.A.
OLDSTONE: State of Viral Genome and Proteins During
Persistent Lymphocytic Choriomeningitis Virus Infection
D.H. WALKER and F.A. MURPHY: Pathology and Patho-
genesis of Arenavirus Infections
Subject Index
Arenaviruses
Biology and Immunotherapy
Edited by M. B. A. Oldstone
With 33 Figures
Springer-Verlag
Berlin Heidelberg NewY ork
London Paris Tokyo
MICHAEL B.A. OWSTONE, M.D.
Department of Immunology
Scripps Clinic and Research Foundation
10666 North Torrey Pines Road
La Jolla, CA 92037, USA
ISBN-13: 978-3-642-71728-4 e-ISBN-13: 978-3-642-71726-0
DOl: 10.1007/978-3-642-71726-0
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© Springer-Verlag Berlin Heidelberg 1987
Softcover reprint of the hardcover I st edition 1987
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Table of Contents
M.B.A. OLDSTONE: The Arenaviruses-
An Introduction . . . . . . . . . 1
e.J. PETERS, P.B. JAHRLING, C.T. Lm, R.H. KENYON,
K.T. McKEE JR., and J.G. BARRERA ORO:
Experimental Studies of Arenaviral Hemorrhagic
Fevers. With 7 Figures . . . . . . . . . . 5
J.B. MCCORMICK: Epidemiology and Control of
Lassa Fever. With 1 Figure . . . . . .. .. 69
M.C. WEISSENBACHER, R.P. LAGUENS, and C.E.
COTO: Argentine Hemorrhagic Fever. With 1
Figure . . . . . . . . . . . . . . . . 79
C.R. HOWARD: Neutralization of Arenaviruses by
Antibody. With 3 Figures . . . . . . . . .. 117
J.E. ALLAN, J.E. DIXON, and P.e. DOHERTY: Nature
of the Inflammatory Process in the Central
Nervous System of Mice Infected with
Lymphocytic Choriomeningitis Virus. With 5
Figures . . . . . . . . . . . . . . . .. . 131
O. MARKER and A.R. THOMSEN: Clearance of Virus
by T Lymphocytes Mediating Delayed Type
Hypersensitivity. With 6 Figures . . . . . . . . 145
R.M. WELSH: Regulation and Role of Large
Granular Lymphocytes in Arenavirus Infections 185
M.B.A. OLDSTONE: Immunotherapy for Virus
Infection. With 10 Figures ..... ... 211
S.P. FISHER-HoCH and J.B. MCCORMICK:
Pathophysiology and Treatment of Lassa Fever 231
Subject Index 241
Indexed in Current Contents
List of Contributors
You will find the addresses at the beginning of the
respective contribution
ALLAN, J.E. 131 Lru, C.T. 5
BARRERA ORO, J.G. 5 MARKER, O. 145
COTO, e.E. 79 MCCORMICK, J.B. 69, 231
DIXON, J.E. 131 McKEE K.T., JR. 5
DOHERTY, P.C. 131 OLDSTONE, M.B.A. 1, 211
FISHER-HoCH, S.P. 231 PETERS, C.J. 5
HOWARD, C.R. 117 THOMSEN, A.R. 145
JAHRLING, P.B. 5 WEISSENBACHER, M.e. 79
KENYON, R.H. 5 WELSH, R.M. 185
LAGUENS, R.P. 79
The Arenaviruses - An Introduction
M.B.A. OLDSTONE
Viruses are generally studied either because they cause significant human, animal
or plant disease or for their utility as materials to probe a basic phenomenon
in biology, chemistry, genetics or molecular biology. Arenaviruses are unusually
interesting in that they occupy both of these categories.
Arenaviruses cause severe human diseases known primarily as the hemor-
rhagic fevers occurring in South and Latin America (Bolivia: Machupo virus
and Argentina: Junin virus) and in Africa (Lassa virus). Because such viruses
produce profound disability and may kill the persons they infect, they are a
source of economic hardship in the countries where they are prevalent. Further,
they provide new problems for health care personnel owing to the narrowing
of the world as visitors from many countries increasingly travel to and from
these endemic areas. In addition, lymphocytic choriomeningitis virus (LCMV)
can infect humans worldwide, although the illness is most often less disabling
than those elicited by other arenaviruses. Yet LCMV is likely of greater concern
to non-arena-virologists and experimentalists using tissue culture or animals,
i.e., workers in molecular biology, cancer research, virology, immunobiology,
etc., because normal appearing cultured cells or tissues and animals used for
research may be persistently infected with LCMV without manifesting clinical
disease or cytopathology and transmit that infection to laboratory workers
(reviewed OLDSTONE and PETERS 1978). For example, HINMAN et al. (1975) re-
corded 48 cases among personnel in the radiotherapy department and vivarium
at the University of Rochester School of Medicine. These persons had contact
with Syrian hamsters into which tumors, unknown to be occultly infected with
LCMV, were transferred. These tumors were obtained from an outside research
supplier who distributed tumor cell lines to numerous laboratories primarily
interested in SV -40 and polyoma virus research. In subsequent investigation
of the 22 tumor lines in question, 13 yielded infectious LCMV. Infection was
spread from the experimental area, presumably via air ducts. Similarly, the
Communicable Disease Center, USA, has recorded multiple cases of LCMV
infections in families scattered from the northeast coast of the United States
(New York) to the western region (Reno, Nevada) originating from hamsters
sold by a single supplier in the southeast (Florida). Several investigators found
that their hybridomas making monoclonal antibodies were infected with LCMV.
The mechanism was likely by the use of infected splenic feeder cells obtained
Department of Immunology, Scripps Clinic and Research Foundation, 10666 North Torrey Pines
Road, La Jolla, CA 92037, USA
Current Topics in Microbiology and Immunology, Vol. 134
© Springer-Verlag Berlin· Heidelberg 1987
2 M.B.A. Old stone
Table 1. Recognized Arenavirus diseases of man
Virus Disease Locality Rodent Person to Laboratory
reservoir person model of
and vector trans- human
mission infection
Lymphocytic Grippe, aseptic Probably origi- Mus musculus Never Mouse
chorio- meningitis, oc- nated in Europe, natural host; documented
meningitis casional more now worldwide colonized ro-
severe forms dents, parti-
of meningoence- cularly mice
phalomyelitis and hamster;
dog?
Junin Argentinian Circumscribed Calomys mus- Occasional Guinea pig
hemorrhagic area of Argen- culinus, pos-
fever tina; Buenos sibly others
Aires to northeast
Machupo Bolivian Beni region Calomys Occasional, Rhesus
hemorrhagic of Bolivia callosus particularly monkey
fever spouses; recog-
nized hospital
outbreak
Lassa Lassa fever Western Africa Mastomys Frequent; Squirrel mon-
nataliensis blood con- key, Guinea
tamination pig strain 13
LCMVWEin
guinea pig
from clinically healthy but persistently infected mice purchased from a commer-
cial source. Hence, researchers studying such diverse areas as the molecular
biology of SV4 0, biologic effects of chlamydia, immune responses of mice mak-
ing hybridoma cells or production of ascites fluids have found their preparations
contaminated with LCMV (LEHMANN-GRUBE 1973; WHO Bulletin 1975; GRIM-
WOOD 1983, 1985; VAN DER ZElJST et al. 1983a, b). Thus, experimentalists may
be exposed to the unexpected and potentially dangerous effects of LCMV owing
to its non-cytolytic persistent infection in tissue culture cell lines and experimen-
tal or pet animals. The recognized arenavirus diseases of man, the vectors and
laboratory models used for their study are listed in Table 1.
Study of the biology of LCMV has led to several major advances in contem-
porary virology and immunology. For example, research on both the acute
and persistent infection of mice with LCMV led to the first descriptions of
virus induced immunopathologic disease (ROWE 1954), ofT cell mediated killing
(COLE et al. 1973; MARKER and VOLKERT 1973) and of the two unique and
separate signals necessary for recognition and lysis of virus infected targets
by cytotoxic T lymphocytes (CTLs) (ZINKERNAGEL and DOHERTY 1974). Hence,
study of the LCMV indicated that CTLs kill virus infected targets only when
two conditions are met: recognition of virus specific determinants and matching
of the major histocompatibility complex on the CTL and the infected target
cell. This phenomenon ofMHC restriction, one of the major tenets of contempo-
The Arenaviruses - An Introduction 3
rary immunology, was not only first described by experimentalists working
with LCMV but also its implications were clearly recognized in this setting
(reviewed by ZINKERNAGEL and DOHERTY 1979). Additionally, the components,
kinetics, genetic control and deposition of immune complexes from the circula-
tion into a variety of tissues including renal glomeruli, brain choroid plexus
and blood vessel arteries were explored by utilizing the LCMV model (OLDSTONE
and DIXON 1969). The conclusions were extended to work on numerous RNA
and DNA virus infections as well as infections with other microbial agents
(reviewed OLDSTONE 1975). Recently, by examination of its supposedly benign
effect, LCMV was shown to cause disease not by means of the well-known
anatomical viral induced destruction of infected cells, but rather by disordering
the synthesis of such cells' differentiated products (OLDSTONE et al. 1982; re-
viewed OLDSTONE 1984). These studies in animals indicate that viruses may
cause disease by altering the cells' physiology and function without causing
their destruction. If these findings are applicable to human viruses, in vivo,
we can anticipate much-needed understanding of the mechanisms by which
dysfunctions of endocrine, nervous and immune systems occur.
Arenaviruses obtained their name from arenosus Latin for sandy - on
the basis of characteristic fine granularities seen inside the virion on ultrathin
section (ROWE et al. 1970). To avoid confusion between areno and adeno viruses,
the International Committee on Viral Nomenclature changed the name to arena-
viruses (ROWE et al. 1970).
Recently, the ability of such viruses to cause persistent infection in cultured
cells and animals, as well as their non-cytolytic nature, has been coupled with
the wealth of information known about their biologic activity to inspire intensive
investigation into the molecular control of viral genes and the molecular basis
of arenavirus induced disease. It is the melding of newly obtained information
on the viral chromosomes and gene structure, the proteins encoded by various
viral genes and the ambisense (positive-genomic sense and negative-complemen-
tary sense) organization of the arenavirus genome - particularly as relates to
the molecular basis of viral persistence, tissue tropism, viral gene regulation
and mechanism of pathogenesis and biology of the virus - that led to the
selection of arenaviruses for these two volumes in the Current Topics in Microbi-
ology and Immunology series.
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