Table Of ContentThe
Herpesviruses
Volume 4
IMMUNOBIOLOGY AND
PROPHYLAXIS OF HUMAN
HERPESVIRUS INFECTIONS
THE VmUSES
Series Editors
HEINZ FRAENKEL-CONRAT, University of California
Berkeley, California
ROBERT R. WAGNER, University of Virginia School of Medicine
Charlottesville, Virginia
THE HERPESVIRUSES
Volumes 1-3 • Edited by Bernard Roizman
Volume 4 • Edited by Bernard Roizman and Carlos Lopez
THE REOVIRIDAE
Edited by Wolfgang K. Joklik
THE PARVOVIRUSES
Edited by Kenneth I. Berns
THE ADENOVIRUSES
Edited by Harold S. Ginsberg
THE VIRUSES: Catalogue, Characterization, and Classification
Heinz Fraenkel-Conrat
The
Herpesviruses
Volume 4
IMMUNOBIOLOGY AND
PROPHYLAXIS OF HUMAN
HERPESVIRUS INFECTIONS
Edited by
BERNARD ROIZMAN
University of Chicago
Chicago, Illinois
and
CARLOS LOPEZ
Sloan-Kettering Institute for Cancer Research
New York, New York
PLENUM PRESS • NEW YORK AND LONDON
Library of Congress Cataloging in Publication Data
Main entry under title:
The Herpesviruses.
The Viruses.
Includes bibliographies and indexes.
1. Herpesvirus diseases. 2. Herpesviruses. I. Roizman, Bernard, 1929-
[DNLM: 1. Herpesviridae. QW 165.5.H3 H5637]
RC147.H6H57 1982 616.9'25 82-15034
ISBN-13: 978-1-4615-8023-2 e-ISBN-13: 978-1-4615-8021-8
DOl: 10.1007/978-1-4615-8021-8
© 1985 Plenum Press, New York
Softcover reprint of the hardcover 1st edition 1985
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
Contributors
Lawrence Corey, Department of Laboratory Medicine and Microbiology
and Virology Division, University of Washington, Seattle, Washing
ton 98195
M. A. Epstein, Department of Pathology, University of Bristol Medical
School, Bristol BS8 1T D, England
Anne A. Gershon, New York University School of Medicine, New York,
New York 10016
Martin S. Hirsch, Department of Medicine, Massachusetts General Hos
pital, and Harvard Medical School, Boston, Massachusetts 02114
Eva Klein, Department of Tumor Biology, Karolinska Institutet, S 10401
Stockholm, Sweden
Fran~ois Lebel, Department of Medicine, Massachusetts General Hos
pital and New England Deaconess Hospitals, and Harvard Medical
School, Boston, Massachusetts 02114
K.-N. Leung, Department of Pathology, University of Cambridge, Cam
bridge CB2 1Q P, England
Carlos Lopez, Sloan-Kettering Institute for Cancer Research, New York,
New York 10021
Bernard Meignier, Institut Merieux, Marcy l'Etoile, Charbonnieres les
Bains, France
Joel D. Meyers, Fred Hutchinson Cancer Research Center and the Uni
versity of Washington School of Medicine, Seattle, Washington 98104
v
vi CONTRIBUTORS
A. A. Nash, Department of Pathology, University of Cambridge, Cam
bridge CB2 1Q P, England
Bodil Norrild, Institute of Medical Microbiology, University of Copen
hagen, DK-2100 Copenhagen 0, Denmark
Gary R. Pearson, Section of Microbiology, Mayo Foundation, Rochester,
Minnesota 55905
Stanley A. Plotkin, The Children's Hospital of Philadelphia, The Uni
versity of Pennsylvania, and the Wistar Institute, Philadelphia, Penn
sylvania 19104
Gerald V. Quinnan, Jr., National Center for Drugs and Biologics, Division
of Virology, Office of Biologics, Food and Drug Administration, Be
thesda, Maryland 20205
Harvey Rabin, DuPont Biomedical Products, North Billerica, Massa
chusetts 01862.
Barry T. Rouse, Department of Microbiology, College of Veterinary Med
icine, University of Tennessee, Knoxville, Tennessee 37996
John L. Sullivan, Department of Pediatrics, University of Massachusetts
Medical School, Worcester, Massachusetts 01605
Jean-Louis Virelizier, Groupe d'Immunologie et de Rhumatologie Pedia
riques (INSERM U 132) Hopital Necker-Enfants Malades, 75743 Paris
Cedex 15, France
Georges H. Werner, Rh6ne-Poulenc Sante, Centre de Recherches de Vi try,
94407 Vitry-sur-Seine, France
Richard J. Whitley, Department of Pediatrics and Microbiology, The Uni
versity of Alabama, Birmingham, Alabama 45294
P. Wildy, Department of Pathology, University of Cambridge, Cambridge
CB2 1QP, England
Aurelio Zerial, Rh6ne-Poulenc Sante, Centre de Recherches de Vitry,
94407 Vitry-sur-Seine, France
Preface
'You damn sadist/said mr cummings 'you
try to make people think.'
-Ezra Pound (Canto 89)
What makes herpesviruses unique? It is certainly not the size of their
genomes or the individual features of their reproductive cycle, although
in toto striking features that are exclusive to the herpesviruses abound.
Unquestionably, the pre-eminent feature is the relationship of herpes
viruses with their natural hosts. As described in preceding volumes,
all herpesviruses seem to be able to colonize and to remain in a latent,
nonproductive form for life of their hosts. Once established in the host,
the relationship is best described as that of an armed truce. What happens
when this truce breaks down or when the host encounters the virus for the
first time is the subject of this volume. We have focused primarily on
the five human herpesviruses [herpes simplex virus 1 (HSV-l), herpes
simplex virus 2 (HSV-2), cytomegalovirus (CMV), varicella zoster virus
(VZV) and Epstein-Barr virus (EBV)] because much more is known about
them than about any other herpesviruses, and because it is of interest to
compare both the diversity of manifestations of infections with human
herpesviruses and the spectrum of human responses to these viruses.
This volume summarizes the current knowledge of the pathogenesis
and immunobiology of herpesvirus infections in man and describes new
and developing approaches to prophylaxis and treatment. It contains con
tributions from distinguished research scientists presently engaged at the
forefront of these scientific investigations. Reactivated HSV-2 infections
occur in a large number of otherwise normal individuals, resulting in
recrudescent genital disease. The first chapter of this book presents the
natural history of genital HSV infections, and thus, defines one of the
more common disease problems associated with a human herpesvirus.
The next three chapters describe the natural and adaptive host defense
vii
viii PREFACE
mechanisms thought to be required for protection against HSV infections,
while chapter 5 deals with the damage caused by the same immune re
sponse induced by the virus infection. Chapter 6 defines the cell-mediated
immune responses to CMVand Chapters 7 through 9 are concerned with
the immunobiology of EBV infections in primates and man. Infections
with any of the herpesviruses can be devastating in immunosuppressed
patients and Chapter 10 describes those that are most difficult to deal
with: CMV infections in organ transplant recipients. Chapters 11 and 12
describe patients with inherited host defense deficiencies, which make
them unusually susceptible to severe disease caused by herpesviruses.
Chapters 13 through 16 describe the current status of vaccine develop
ment for the herpesviruses. Finally, Chapters 17 through 19 focus on,
antiviral chemotherapy, interferon therapy, and immunopotentiators.
It is the understandable wish of editors of volumes such as this that
their compilations serve a useful and lasting reference to the current state
of knowledge. We are not immune to such thoughts, but the best way
we can thank the contributors for their efforts and especially for the
timeliness of their contributions is to wish this volume a precocious
obsolescence through their efforts.
Bernard Roizman
Carlos Lopez
Chicago, Illinois
New York, New York
Contents
Chapter 1
The Natural History of Genital Herpes Simplex Virus:
Perspectives on an Increasing Problem
Lawrence Corey
I. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1
II. History ....................................... 1
III. Epidemiology of Genital Herpes .................... 2
A. Prevalence of Genital HSV Infections ............. 2
B. Evidence for an Increasing Prevalence of Infection ... 3
C. Prevalence of HSV Antibody .................... 4
D. Incidence of Genital Herpes. . . . . . . . . . . . . . . . . . . . . 6
E. Comment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
IV. Clinical Manifestations of Genital Herpes. . . . . . . . . . . . . 7
A. First Episodes of Genital Herpes ................. 7
B. Primary Genital Herpes .... . . . . . . . . . . . . . . . . . . . . 8
C. Complications of Genital Herpes . . . . . . . . . . . . . . . .. 13
D. Summary of the Clinical Course of First Episodes of
Genital Herpes. . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 17
E. Future Directions for Research on the Clinical
Manifestations of Genital Herpes ................ 18
F. Recurrent Genital Herpes ...................... 19
G. Other Clinical Syndromes Associated with Genital
HSV Infection ............................... 20
V. Chronicity of Genital HSV Infections ................ 23
VI. Sexual Transmission of Genital HSV . . . . . . . . . . . . . . . .. 27
VII. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 28
References ........................................... 29
ix
x CONTENTS
Chapter 2
Natural Resistance Mechanisms in Herpes Simplex Virus
Infections
Carlos Lopez
I. Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 37
II. Genetic Resistance to Lethal HSV-1 in the Mouse ...... 40
III. Genetic Resistance to Lethal HSV-2 in the Mouse ...... 43
IV. Genetic Resistance to HSV-2-Induced Hepatitis ........ 43
V. Macrophages ................................... 43
A. Role of Macrophages in Resistance to HSV -1 in the
Mouse ..................................... 44
B. Role of Macrophages in Resistance to HSV-2 in the
Mouse ..................................... 46
C. Role of Macrophages in Resistance to HSV-2-Induced
Hepatitis ................................... 47
D. Role of Macrophages in Resistance to HSV-1 and HSV-
2 in Man ................................... 48
VI. Natural Killer Cells. . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 49
A. Heterogeneity of NK Cells . . . . . . . . . . . . . . . . . . . . .. 50
B. Cell Lineage of NK(HSV-Fs) Effectors ............. 52
C. Role of IFN in NK(HSV-Fs) Response. . . . . . . . . . . . .. 53
D. NK Cells Limit HSV-1 Replication in Vitro. . . . . . . .. 53
E. Role of NK Cells in Resistance to HSV -1 in the
Mouse ..................................... 54
F. Low NK(HSV-Fs) Function Associated with
Susceptibility to Herpesvirus Infections in Man ..... 55
VII. Interferon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 57
A. Role of IFN in Genetic Resistance to HSV-1 in the
Mouse ..................................... 57
B. IFN-a-Generating Cells in Man .................. 58
C. Role of IFN in Resistance to Herpesvirus Infections in
Man ....................................... 59
VIII. Concluding Remarks ............................. 60
References ........................................... 60
Chapter 3
Humoral Response to Herpes Simplex Virus Infections
Bodil NOllild
I. Introduction .................................. " 69
II. HSV-Specific Antibodies in Human Convalescent Sera. .. 70
III. Measurement of HSV-Specific Neutralizing Antibodies. " 71
