Cytomegalovirus: Biology and Infection

447 Pages·1991·13.646 MB·English

by  Monto Ho M.D. (auth.)

Cytomegalovirus
Biology and lnfection
SECOND EDITION
Cytomegalovirus
Biology and lnfection
SECOND EDITION
Monto Ho, M. D.
Graduale Schoo/ of Public Health and School of Medicine
University of Pittsburgh
and
Presbyterian-University Hospital
Pittsburgh, Pennsylvania
Springer Science+Business Media, LLC
L1brary of Congrass Catalog1ng-1n-Publ1cat1on Data
Ho, Monto.
Cytolegalovirus : biology and 1nfect1on I Monto Ho. --2nd ed.
p. CN.
Includes b1bl1ograph1cal references and 1ndex.
ISBN 978-I-4757-9944-6 ISBN 978-1-4757-9942-2 (eBook)
DOI 10.1007/978-1-4757-9942-2
1. Cytomega1ov1rus 1nfect1ons. 2. Cytomega1ov1ruses. I. Title.
IDNLM: 1. Cytomega11c Inclusion Disease. 2. Cytomegaloviruses.
QH 165-5.H3 H678cl
RC136.8.H6 1991
616.9'25--dc20
DNLMIDLC
for Library of Congress 90-14345
CIP
© 1991, 1982 Springer Science+Business Media New York
Originally published by Plenum Publishing Corporation New York in 1991
Softcoverreprintofthehardcover 2nd edition 1991
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 to the First Edition
Although there are a number of excellent current reviews on one or another aspect of
cytomegalovirus, the last comprehensive treatment of this subject was that of Krech
et al. (197la). In view of the amazing advances in the virological, epidemiologic,
and clinical knowledge of cytomegaloviruses, an up-to-date book is needed. Such a
work should cover many areas of expertise and a voluminous technical literature.
Each area might have been reviewed and analyzed by workers more expert than
myself. However, I have embarked on the entire venture alone in order to attain unity
and continuity in this book, characteristics that are not easily achieved in the more
popular multiauthored works.
I have tried to review the Iiterature and provide a critical summary for each area
discussed. To do this, I provide as much of the primary data of the relevant works as
needed and not just the qualitative conclusions. Inevitably, the flow of the narrative
may be interrupted by dry facts and figures. However, such information is essential
to make this a meaningful reference work. But for those not interested in such
details, I have provided at what I hope are crucial points critiques and summaries.
This book is not an exhaustive review of all the literature. This is probably no
Ionger possible or even desirable. By selection, however, one runs the risk of having
missed or ignored important papers. I am keenly aware of this, and I wish to
apologize for such oversight, if that is possible.
I visualize this work as being useful for physicians, scientists, and students
interested in the biology of and infection by human cytomegalovirus. I feel that to
understand these, the basic virology of this virus and related herpesviruses must be
included. Topics that have not advanced a great deal and that are adequately de
scribed in available works, such as the anatomic pathology, have not been reviewed
in detail. The emphasis has been placed on newer insights in the virology, immu
nology, serology, epidemiology, and especially clinical aspects of human
cytomegalovirus. I wish tobring out the interactions of knowledge in these areas.
Part II is a much shorter treatment of the nonhuman cytomegaloviruses, reviewed
primarily from the point of view of their contribution to the understanding of the
human virus.
V
vi Preface to the First Edition
Finally, I wish to thank Drs. Charles R. Rinaldo, Jr., John A. Armstrong, and
Donald N. Medearis for their critical review of the manuscript. Their suggestions
were invaluable. Dr. John N. Dowling's thorough review of CMV infection in
patients with malignancies was the basis of Section 13.4. I also acknowledge the
indispensable and patient secretarial assistance of Ms. Betty Edwards and Hannah
Grace.
Monto Ho, M.D.
Pittsburgh, Pennsylvania ( 1981)
Preface to the Second Edition
The remarkable medical events and advances in knowledge that have taken place
since publication of the ·first edition in 1982 have made a thorough revision of this
book necessary. Opportunistic cytomegalovirus (CMV) inf~ctions have multiplied
in numbers and complexity with the explosion of AIDS on the medical scene and the
increase in other iatrogenic and natural deficiency states. At the same time, ad
vances in modern virology and immunology have been such that all our previous
assumptions have badtobe scrutinized or revised in their light. Thus, although the
original structure of the book has been maintained, almost every page or section of
the text has been edited, revised, or expanded. In addition, we are indeed fortunate
to have Drs. MarkStinski and Lucy Rasmussen each write a new chapter, one on the
molecular biology and the other on the gene products of CMV. They provide
authoritative treatments of these critical subjects, which I have tried to incorporate
and fit into the unity and continuity of the book that were hallmarks of the uni
authored first edition.
This work is still designed to be a critical, comprehensive, but not exhaustive
review. It is intended tobe useful for physicians, scientists, and students interested
in the biology and infection by human cytomegalovirus. I would like to thank Ms.
Peg Corbett, Christine Hallahan, and Betty Edwards for their patient secretarial
assistance.
Monto Ho, M.D.
Pittsburgh, Pennsylvania
vii
Contents
List of Abbreviations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . xvn
Chapter 1. History of Cytomegalovirus ........................... .
1. 1. Period of Cytopathology (1905-1956) ........................ .
1.2. Virological Period . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
1. 3. Recent Trends . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5
Chapter 2. Molecular Biology of Cytomegalovirus Replication . . . . . . . . 7
by MarkStinski
2.1. Introduction 7
2.2. Structure and Organization of the Viral Genomes ............... . 8
2.2.1. Isomerizing and Nonisomerizing Genomes ............. . 8
2.2.2. Comparisons between Different Strains of Human CMV .. . 9
2.2.3. Animal CMV DNAs ............................... . 10
2.2.4. Homology with Cellular DNA ....................... . 10
2.2.5. Defective Viral DNA .............................. . 10
2.3. Cis-Acting Elements Associated with the Viral Genomes . . . . . . . . . 11
2.4. Transcription . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.4.1. Immediate Early (a) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14
2.4.2. Early (ß) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
2.4.3. Late (-y) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16
2.4.4. Organization and Expression of the IE1 and IE2 Genes . . . . 17
2.5. Functions of the lEI and IE2 Gene Products . . . . . . . . . . . . . . . . . . . . 18
2.5.1. The lEI Protein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18
2.5.2. Transactivation of Early Viral Promoters by IE2 Proteins 20
2.5.3. Negative Regulation of the Major IE Promoter by IE2
Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21
ix
x Contents
2.5.4. Sites in the Major IE Promoter-Regulatory Region Required
for Negative Regulation by IE2 . . . . . . . . . . . . . . . . . . . . . . . 21
2.6. Early (ß) Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22
2.7. Late ('Y) Structural Genes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 25
2.8. Viral DNA Synthesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31
2.8.1. The Viral DNA Polymerase . . . . . . . . . . . . . . . . . . . . . . . . . . 31
2.8.2. The Rate of Human CMV DNA Synthesis . . . . . . . . . . . . . . 32
2.8.3. The Model for DNA Replication . . . . . . . . . . . . . . . . . . . . . . 32
2.9. Expression in Nonpermissive (Nonproductive) Cells . . . . . . . . . . . . . 34
Chapter 3. Gene Products of Cytomegalovirus and Their Immunologie
Significance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
by Lucy E. Rasmussen
3.1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
3.2. Intracellular Viral Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
3.2.1. Immediate Early (a) Proteins . . . . . . . . . . . . . . . . . . . . . . . . . 38
3.2.2. Early (ß) Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 38
3.2.3. Late ('Y) Proteins: The 51-kDa DNA-Binding Protein . . . . . . 39
3.3. Structural Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39
3.3.1. Development of Virions and Enveloped Infectious Virus . . . 39
3.3.2. Proteins Associated with Extracellular Virion Forms . . . . . . 41
3.4. Envelope Glycoproteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 43
3.4.1. The gB Homologue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 44
3.4.2. The gH Homologue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 46
3.4.3. The gC II Glycoprotein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47
3.4.4. Integral Membrane Glycoprotein . . . . . . . . . . . . . . . . . . . . . . 48
3.4.5. The gp48 Glycoprotein . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 48
3.5. Proteins Identified by Sequence Analysis Only . . . . . . . . . . . . . . . . . . 48
3.5.1. The MHC Class I Antigen Homologue . . . . . . . . . . . . . . . . . 48
3.5.2. Phosphotransferase . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
3.6. Plasma Membrane Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
3.7 Virus-Induced Host Cell Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
3. 7. l. Class I HLA Molecules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49
3. 7 .2. Fe Receptors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 50
3.8. Immune Responses to CMV Gene Products in Humans . . . . . . . . . . . 51
3.8.1. Viral Gene Products That Stimulate Humoral Immunity . . . 51
3.8.2. Viral Gene Products That Stimulate Cellular Immunity . . . . 54
3.9. Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 56
Chapter 4. Characteristics of Cytomegalovirus . . . . . . . . . . . . . . . . . . . . . 57
4.1. Herpesviridae . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 57
4.2. Cytomegalovirus and Other Human Herpesviruses . . . . . . . . . . . . . . . 60
Contents xi
4030 Morphological Events of Replication 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 62
403010 Early Antigensand Cytopathology 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 64
403020 Nuclear Changesand Nucleocapsid Formation 0 0 0 0 0 0 0 0 0 0 0 65
403030 Cytoplasmic lnclusions and Dense Bodies 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 66
4040 Biochemical Events in Infected Cells 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 68
4.4010 Protein and DNA Synthesis 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 68
4.4020 Induction of Enzymes 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 69
4o5o Stability of Cytomegalovirus 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 70
4 05 ol. Stability of Cytomegalovirus at Different Temperatures 0 0 0 0 71
405020 Stability of Cytomegalovirus in Urine or Blood 0 0 0 0 0 0 0 0 0 0 72
Chapter 5o Virological Diagnosis and lnfections in Cells
and Tissues 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 75
501. Virological Diagnosis of Cytomegalovirus Infection 0 0 0 0 0 0 0 0 0 0 0 0 0 0 75
501.1. Routine Virus Assay 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 75
501.20 Virological Diagnosis in the Presence of Antibody 0 0 0 0 0 0 0 0 77
501030 Rapid Virus Assay 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 80
5o 2 0 Demonstration of CMV by Monoclonal Antiborlies 0 0 0 0 0 0 0 0 0 0 0 0 0 0 82
5030 Demonstration of CMV by Nucleic Acid Hybridization 0 0 0 0 0 0 0 0 0 0 0 83
50301. Polymerase Chain Reaction 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 84
503020 Immediate Early Antigen Transcripts 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 85
5.40 Demonstration of CMV by Other Methods 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 85
5050 Abortive, Persistent, and Latent Infections in Cell Coltures 0 0 0 0 0 0 0 0 87
50501. Infections in Nonhuman Cells 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 87
505020 Infections in Human Epithelial Cells 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 88
505030 Infections of Human Leukocytes 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 89
5o5.4o Persistent Infections in Other Human Cells 0 0 0 0 0 0 0 0 0 0 0 0 0 0 91
505050 "Latent" Infection in Human Cells 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 92
505060 Differentiation of Cells and Permissiveness to CMV 0 0 0 0 0 0 93
5060 Human Cytomegalovirus and Cell Transformation 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 94
50 7 0 Relationship of Human CMV to Cancer 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 96
50 8 0 Human CMV and Atherogenesis 0 0 o 0 o 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 98
Chapter 6° Serologie Tests for Cytomegalovirus lnfections 0 0 0 0 0 0 0 0 0 0 101
601. Introduction 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 101
6020 Camplernent-Fixation Test 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 101
60201. The Nature of Camplernent-Fixation Antigen 0 0 0 0 0 0 0 0 0 0 0 0 102
602020 The Nature of Camplernent-Fixation Antibody 0 0 0 0 0 0 0 0 0 0 0 103
602030 Constancy of the Camplernent-Fixation Titer 0 0 0 0 0 0 0 0 0 0 0 0 104
602040 The Camplernent-Fixation Text in Cytomegalovirus
Infections 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 105
6030 Neutralization Tests 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 107