Table Of ContentIMMUNOBIOLOGY AND
PROPHYLAXIS OF
HUMAN HERPESVIRUS
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
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IMMUNOBIOLOGY AND PROPHYLAXIS OF HUMAN HERPESVIRUS
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IMMUNOBIOLOGY AND
PROPHYLAXIS OF
HUMAN HERPESVIRUS
INFECTIONS
Edited by
Carlos Lopez
Eli Lilly and Company
Indianapolis, Indiana
Ryoichi Mori
Kyushu University
Fukuoka, Japan
Bernard Roizman
The University of Chicago
Chicago, Illinois
and
Richard J. Whitley
University of Alabama at Birmingham
Birmingham, Alabama
PLENUM PRESS • NEW YORK AND LONDON
Library of Congress Cataloglng-In-Publlcatlon Data
International Conference on I.munobiology and Prophylaxis of Human
Herpesvirus Infections (4th: 1989 : Fukuoka-shi, Japan)
Immunobiology and prophylaxis of human herpesvirus infections
edited by Carlos Lopez ... [et al.l.
p. em. -- (Advances in experimental medicine and biology v.
278)
"Proceedings of the Fourth International Conference on
I.munobiology and Prophylaxis of Human Herpesvirus Infections, held
Octbber 4-6, 1989, in Fukuoka, Japan"--T.p. verso.
Includes bibliographical references.
Includes indexes.
ISBN-13: 978-1-4684-5855-8 e-ISBN-13: 978-1-4684-5853-4
001: 10.1007/978-1-4684-5853-4
1. Herpesvirus infections--Immunological aspects--Congresses.
2. Herpesvirus infections--Molecular aspects--Congresses.
3. Herpesvirus infections--Prevention--Congresses. I. Lopez,
Carlos, 1942- II. T.itle. III. Series.
[ONLM: 1. Herpesvirus Infections--diagnosis--congresses.
2. Herpesvirus Infections--immunology--congresses. 3. Herpesvirus
Infections--therapy--congresses. W1 A0559 v. 278 I WC 571 I604i
1989l
CR201.H48I58 1989
DNLM/OLC
for Library of Congress 90-7938
CIP
Proceedings of the Fourth International Conference on
Immunobiology and Prophylaxis of Human Herpesvirus Infections,
held October 4-6, 1989, in Fukuoka, Japan
ISBN-J3: 978-1-4684-5855-8
© 1990 Plenum Press, New York
Softcover reprint of the hardcover 1st edition 1990
A Division of Plenum Publishing Corporation
233 Spring Street, New York, N.Y. 10013
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
Preface
No one whose opinion deserves a moment's consideration can doubt that most of the
great positive evils of the world are in themselves removable, and will, if human affairs
continue to improve, be in the end reduced to narrow limits.
J. S. Mill, Utilitarianism, II, 1863
Mill was not writing about herpesviruses, but had he known them as we do, he would
have included them among the great positive evils of the world. They cause disease and
premature death, and are very costly to our society. There is no loftier aim than to cure
or prevent human infections with these viruses.
The objective of much of the current research on herpesviruses is directed toward an
understanding of the molecular mechanisms involved in initiation of infection, establish
ment and termination of latent state, virus multiplication, and the destruction of cells
which ultimately is the basis of the diseases caused by these viruses. At no time during the
past 80 years, since members of the herpesvirus family were first discovered, has there
been so much progress in our understanding of the biology of these viruses as in the past
few years. Along with the development of a greater understanding of the molecular biol
ogy of the well-known herpesviruses we have witnessed the isolation of new human herpes
viruses. This book deals with the new viruses and the molecular basis of diseases caused
by viruses that have been known to us for some time, with diagnostic tools, current or
promising therapeutic agents, and vaccination. It reflects not merely the results of current
research but also the current ideas in the field. Without the efforts of the contributors of
this book, there would be no hope of reducing the threat of infection with these agents,
and to them we dedicate this book. While the book reflects the scientific advances of the
field, its format and organization are the work of Erik Carlson, the true editor of this
volume.
The Editors
April, 1990
v
Contents
Human Herpesvirus No.6
Niza Frenkel, Ehud Roffman, Eric C. Schirmer, George Katsafanas,
Linda S. Wyatt, and Carl H. June
Cellular and Growth-Factor Requirements for the Replication of Human
Herpesvirus 6 in Primary Lymphocyte Cultures . . . . . . . . . . . . . . . . . . . . . . . .. 1
Philip E. Pellett, Gary J. Lindquester, Paul Feorino, and Carlos Lopez
Genomic Heterogeneity of Human Herpesvirus 6 Isolates ................ 9
Shiro Nii, Mariko Yoshida, Fumio Uno, Takeshi Kurata, Kazuyoshi Ikuta,
and Koichi Yamanishi
Replication of Human Herpesvirus 6 (HHV-6): Morphological Aspects ..... 19
Koichi Yamanishi, Toshio Kondo, Kazukiro Kondo, Yasuhiko Hayakawa,
Shinichi Kido, Kazuo Takahashi, and Michiaki Takahashi
Exanthem Subitum and Human Herpesvirus 6 (HHV- 6) Infection ......... 29
T. Kurata, T. Iwasaki, T. Sata, T. Wakabayashi, K. Yamaguchi, T. Okuno,
K. Yamanishi, and Y. Takei
Viral Pathology of Human Herpesvirus 6 Infection . . . . . . . . . . . . . . . . . . . .. 39
Immunobiology of Varicella-Zoster Virus
Michiaki Takahashi, Koichi Baba, Kiyoshi Horiuchi, Hitoshi Kamiya,
and Yoshizo Asano
A Live Varicella Vaccine . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 49
Lawrence D. Gelb, Susan G. Adams, and Dennis E. Dohner
Differentiation between the Oka Varicella Vaccine Virus
and American Wild-Type Varicella-Zoster Virus (VZV) ................. 59
Ann M. Arvin, Celine M. Koropchak, Margaret Sharp. Randy Bergen,
and Pamela S. Diaz
The T-Lymphocyte Response to Varicella-Zoster Viral Proteins ........... 71
Paul R. Kinchington, Paul Ling, Michael Pensiero, Ann Gershon, John Hay,
and William T. Ruyechan
A Possible Role for Glycoprotein gp V in the Pathogenesis of
Varicella-Zoster Virus .......................................... 83
vii
viii Contents
Human Cytomegalovirus
Sergio Stagno and Gretchen A. Cloud
Changes in the Epidemiology of Cytomegalovirus . . . . . . . . . . . . . . . . . . . . .. 93
Takami Tomiyama and Yasuhiko Masuho
Antiviral Activities of a Human Monoclonal Antibody against Human
Cytomegalovirus ............................................. 105
Epstein-Barr Virus
Robert Orlowski and George Miller
Topological Effects of EBNA 1 on oriP 115
Meihan Nonoyama, L-T. Wen, Akiko Tanaka, and Guy Bradley
Detection of 12-0-Tetradecanoylphorbol-13-Acetate-induced Cellular
Proteins That Compete with the Epstein-Barr Virus Nuclear Antigen 1
(EBNA-1) for Binding to a Site within the Epstein-Barr Virus oriP . . . . . . .. 125
A. B. Rickinson
On the Biology of Epstein-Barr Virus Persistence: A Reappraisal. . . . . . . .. 137
T. Osato, S. Imai, T. Kinoshita, T. Aya, M. Sugiura, S. Koizumi, and F. Mizuno
Epstein-Barr Virus, Burkitt's Lymphoma, and an African Tumor Promoter 147
Herpes Simplex Virus
Myron Levine, Alexandra Krikos, Joseph C. Glorioso, and Fred L. Homa
Regulation of Expression of the Glycoprotein Genes of Herpes
Simplex Virus Type 1 (HSV-1) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 151
Lenore Pereira, Ishtiaq Qadri, David Navarro, and Concepcion Gimeno
Antigenic and Structural Properties of Mutants in Herpes Simplex
Virus 1 Glycoprotein B ........................................ 165
Yoichiro Kino
Yeast-derived Glycoprotein B-1 of Herpes Simplex Virus (HSV)
as a Candidate for an HSV Vaccine ............................... 183
Ryoichi Mori, Hiroko Minagawa, Shunji Sakuma, Shirou Mohri,
and Takeshi Watanabe
Herpes Simplex Virus Type 1 Infection in Mice with Severe
Combined Immunodeficiency (SCID) .............................. 191
Herpes Simplex Virus Latency
Jack G. Stevens
Transcripts Associated with Herpes Simplex Virus Latency . . . . . . . . . . . . .. 199
Y. Jerold Gordon
Pathogenesis and Latency of Herpes Simplex Virus Type 1 (HSV-1):
An Ophthalmologist's View of the Eye as a Model for the Study
of the Virus-Host Relationship ................................... 205
Contents ix
Amy E. Sears
Mechanisms of Restriction of Viral Gene Expression during Herpes
Simplex Virus Latency ................•..•..................... 211
Diagnostics
Steven Wolinsky, Jan Andersson, and Anne Rowley
Detection of a Highly Conserved Region of Herpesviridae DNA by
In Vitro Enzymatic Amplification: Application to the Detection
of a New Human Herpesvirus .................................... 219
Karen V. Spiezia, Bruce J. Dille, Isa K. Mushahwar, Lemma Kifie,
and Greg F. Okasinski
Prevalence of Specific Antibodies to Herpes Simplex Virus Type 2
as Revealed by an Enzyme-linked Immunoassay and Western
Blot Analysis .. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 231
Chemotherapy of Herpesvirus Infections
Richard J. Whitley, Mark Middlebrooks, and John W. Gnann, Jr.
Acyclovir: The Past Ten Years . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 243
Haruhiko Machida
Brovavir: Its Antiherpesviral Activity and Mode of Action .............. 255
Michihito Niimura
A Double-Blind Clinical Study in Patients with Herpes Zoster
to Establish YN-72 (Brovavir) Dose ............................... 267
Joanne J. Bronson, Louis M. Ferrara, Michael J. M. Hitchcock, Hsu-Tso Ho,
Kathleen L. Woods, Ismail Ghazzouli, Earl R. Kern, Kenneth F. Soike,
and John C. Martin
(S)-1-(3-Hydroxy-2-(phosphonylmethoxy )propyl )cytosine (HPMPC):
A Potent Antiherpesvirus Agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 277
Conclusions
Bernard Roizman
Whither Herpesviruses? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 285
Author Index ............................................. '.' . . . . .. 293
Subject Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 295
Cellular and Growth-Factor Requirements for the
Replication of Human Herpesvirus 6 in Primary
Lymphocyte Cultures
Niza Frenke!/'· Ehud Roffman/ Eric C. Schirmer/ George Katsafanas/
Linda S. Wyatt/ and Carl H. June2
'Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases/Twinbrook,
National Institutes of Health, 12441 Parklawn Drive, Rockville, Maryland 20852; and 2Naval
Medical Research Institute, Bethesda, Maryland 20814
Introduction
Human herpesvirus 6 (HHV-6) was first isolated in 1986 from peripheral blood of
AIDS patients and patients with lymphoproliferative disorders (1). Yamanishi and co
workers (2, 3) have further shown that HHV-6 is the causative agent of exanthem subitum
(roseola infantum), a common childhood disease characterized by high fever and skin rash.
Analyses of HHV-6 cell tropism have yielded complex results. The GS strain isolated by
Salahuddin et a1. (1) was shown to replicate in a variety of established cell lines including
B cells positive for Epstein-Barr virus, continuous T-cell lines, megakaryocytes, and glio
blastoma cells (4). Other HHV-6 strains were reported to replicate in continuous T-cell
lines (5, 6). In contrast, the Z29 strain does not readily replicate in these cells (7, 8).
While more quantitative studies are needed to evaluate the relative efficiencies of virus
replication in different cell types, it is commonly accepted that HHV-6 isolates readily
replicate in T cells (5-7, 9). Moreover, Takahashi et a1. (10) reported that HHV-6 isolates
infect predominantly CD4 + T cells in the peripheral-blood lymphocytes (PBL) of exanthem
subitum patients.
As part of our studies of HHV-6 replication we began a series of experiments designed
to elucidate cellular and molecular requirements for virus replication. Since the T lym
phocyte is a quiescent, nondividing cell unless activated by a specific antigen or nonspecific
mitogens, we have asked whether T-cell activation was a prerequisite for HHV-6 replica
tion, and whether the efficiency of virus propagation was affected by interleukin 2 (IL-2).
The results of these studies are reviewed below.
Results
HHV-6 Replication is Enhanced by T-Cell Activation
Three sets of studies revealed that T-cell activation enhances HHV-6 replication and
that efficient virus replication occurs only in host cells capable of responding to cell activa
tion signals.
In the first study (L. S. Wyatt, N. Balachandran, and N. Frenkel, manuscript in prepara-
·Corresponding author.
Immunobiology and Prophylaxis of Human Herpesvirus Infeclions
Edited by C. Lopez el al., Plenum Press, New York, 1990 1
2 N. Frenke~ E. Roffman, E. C. Schirmer, G. Katsafanas, L. S. Wyatt, and C. H. June
tion) virus replication was compared in nonactivated PBL and in PBL exposed to the
polyclonal T-cell mitogen phytohemagglutinin (PHA). We employed in this work the
HHY-6 strain U1102, isolated by Downing et ill. (5), and strain Z29, isolated by Lopez et
al. (7). The two strains differed in their ability to propagate in continuous cell lines.
Thus, the U1102 strain was shown to replicate readily in T-cell lines (5), whereas the Z29
strain does not replicate in many of these cell lines (8, and L. S. Wyatt and N. Frenkel,
unpublished results). Replication efficiency in the activated and nonactivated PBL was
assessed by viral cytopathic effects (CPB), the yields of infectious virus, the accumulation
of viral DNA, and the presence of viral antigens as determined by immunofluorescence
(IF) assays employing an HHY-6 monoclonal antibody (11). These analyses are exempli
fied in figure 1 with data from the infectious virus yields. The results show that the repli
cation of the UII02 and Z29 strains in fresh peripheral-blood lymphocytes is significantly
enhanced by T-cell activation.
107 Z29
106
105
PBL(P)P
104
103 PBL(P)N
...... PBL(N)N
~ <102
Q - 0 2 4 6 8 10 12
It)
C
(3
I- 107 U1102
PBL(P)P
106
105 PBL(P)N
104 PBL(N)N
103
<102
- 0 2 4 6 8 10 12
DAY POST-INFECTION
Figure 1. Infectious virus yield of HHV-6 strains in nonactivated and activated PBL cultures. PBL cultures
were incubated in the absence or in the presence of PHA prior to infection with HHV-6 strains UU02 and
Z29. PBL(N)N = no PHA present prior to or during infection; PBL(P)N = PHA present only prior to infec
tion; PBL(P)P = PHA present prior to and during infection. Data are from L. S. Wyatt, N. Balachandran, and
N. Frenkel (manuscript in preparation).
