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Herpesviruses, classified in the family Herpesviridae, are
important human and animal pathogens that can cause primary, latent
or recurrent infections and even cancer. The major interest in
research on herpesviruses today focuses on understanding the
organization of the DNA genome, as well as on characterizing the
viral genes in regard to their control and function. Modern
techniques have allowed the viral DNA to become a molecular tool in
the study of gene function, since it is now possible to implant the
DNA into eukaryotic cells. This book contains original studies on
the structure and organization of the DNA of human and animal
herpes viruses. The various chapters acquaint the reader with the
organization of the viral DNA, the mRNA transcripts, the
replicative intermediates of the viral DNA, defective DNA genomes
and their mode of synthesis, analyses of the viral DNA sequences in
transformed cells, and the relationship between the presence of
viral DNA fragments in the cancer cells and the transformed state
of the cells."
Over the generations the skin has been the site for immunization
against smallpox. This method of immunization was described in a
letter written by Lady Mary Montagu on April 1, 1717 in
Adrianopole, Turkey: "The small-pox, so fatal, and so general
amongst us, is here entirely harmless by the invention of
ingrafting, which is the term they give it. . . The old woman comes
with a nut-shell full of the matter of the best sort of small-pox .
. . She immediately rips open (the skin) with a large needle . . .
and puts into the vein as much venom as can lie upon the head of
her needle, and after binds up the wound. There is no example of
anyone that died of it; and you may believe that I am satisfied of
the safety of this experiment since I intend to try it on my dear
little son" (Letters from the right Honourable Lady Mary Montagu
1709-1762. Published by J. M. Dent and Co. London, 2nd edition,
September, 1906, p. 124. ) The "variolation" method was, 80 years
later, markedly improved by the use of cowpox virus, as reported by
Edward Jenner in 1796. The successful method of intradermal
immunization against smallpox and later against other virus
diseases is in fact based on the presence of anitigen-presenting
dendritic cells in the skin.
The basis for the effective treatment and cure of a patient is the
rapid diagnosis of the disease and its causative agent, which is
based on the analysis of the clinical symptoms coupled with
laboratory tests. Although rapid advance ments have been made in
the laboratory diagnosis of virus diseases, the neces sary
isolation of the causative virus from the clinical specimens is a
relatively long procedure. Viruses which integrate into the
cellular DNA (such as human immunodeficiency virus, HIV -1, or
hepatitis B virus) are difficult to identify by molecular
techniques, while viruses which exist in the clinical material in
low concentrations are even more formidable to identify. Recently,
the application of the polymerase chain reaction (peR) technique
developed by K. D. Mullis and detailed in the study by Saiki et al.
(1985) led to a revolution in virus diagnosis. The peR technique
was rapidly applied to the diagnosis of viruses in clinical
material. Volume 1 of Frontiers of Virology provides new
information on the advan tages of the use of the peR for the
diagnosis of many human disease-causing viruses, as well as on some
problems with its use."
In this book the current knowledge on human cytomegalovirus (HCMV)
as a human pathogen is lucidly summarized, bringing the reader
fully up to date with current knowledge concerning HCMV and all the
known clincial and medical aspects of diseases caused by, and
associated with, HCMV. The book is divided into four parts: (I)
Human cytomegalovirus and human diseases; (II) human
cytomegalovirus infections and the immunocompromised host; (III)
diagnosis, treatment, and prevention of human cytomegalovirus and
human diseases; and (IV) molecular aspects of human
cytomegalovirus. Each part is put together from chapters written by
experts in the respective fields, providing basic medical and
molecular knowledge in addition to more specific understanding of
HCMV infections.
Six members of the Herpesviridae family are human pathogens,
including herpes and 2 (HSV-I and 2), Epstein-Barr virus (EBV),
varicella zoster simplex virus I virus (VZV), human cytomegalovirus
(HCMV), and human herpesvirus 6 (HHV 6). Each of these viruses is
capable of causing distinct diseases of varying severity in
children, young adults, and the aged. The diseases range from
infection of epithelial tissue to the infection of internal organs
and white blood cells. A common feature of the six pathogenic human
herpesviruses is their ability to latently infect different cell
types in which the viral DNA is not integrated and is unable to
express its pathogenicity. Reactivation of the herpesviruses is a
result of cellular processes which reactivate viral genes, leading
to virus progeny and to signs of infection. Due to their ability to
become latent after initial infection, once the pathogenic
herpesviruses infect children they are maintained throughout life,
having the potential of cause various diseases upon reactivation.
This book was written during a period when the technologies of
genetic engineering were being applied to the study of animal
viruses and when the organization and function of individual virus
genes were being elucidated. This book, which uses human and animal
viruses as models, aims to under stand the developments in
molecular virology during the last 20 years. Al though molecular
virology could also be taught by means of bacteriophages or plant
viruses, the advantage of using animal viruses is in their ability
to cause human and animal diseases as well as to transform cells, a
primary problem in medicine. For the sake of clarity and
convenience, not all the individual contributors to the various
aspects of molecular virology were cited in the text. Instead, the
reader is referred to review articles or key papers that list the
numerous excel lent publications that have contributed to
clarification of the various molecular processes. Thus the
end-of-chapter bibliographies will guide the reader to the
publications in which the original contributing authors are quoted.
References given under the heading Recommended Reading are intended
to assist those interested in pursuing a given subject further. I
hope that this book will fulfill the purpose for which it is
designed, and I urge readers to contact me if errors are found or
updating is required."
Research on antiviral drugs and their mode of action in infected
cells. in animals and in man. has led to a better understanding of
the molecular pro cesses involved in virus replication. Screeninq
of large numbers of natural and semisynthetic compounds resulted in
the characterization of certain sub stances that had a limited
efficiency as antiviral druqs. A few chemically synthesized
compounds were also found to be effective as antiviral agents in
the chemotherapy of human virus diseases. A major difficulty in the
develop ment of effective antiviral agents has been the lack of
selectivity. and toxicity for uninfected cells. of drugs that
effectively inhibited virus replication in vitro. Further
understanding of the molecular processes of virus replication in
infected cells has resulted in the development of new antivirals
directed at virus-coded enzymes or proteins. Recent studies on
antivirals that are activated by the herpes simplex virus type
l-coded thy midine kinase from a prod rug to an antiviral drug have
opened new directions in the development of effective antiviral
drugs. The present book deals with a number of antiviral drugs
effective against herpes simplex viruses and provides some insight
into the molecular aspects of virus replication. It also throws
light on the new approaches to the development of antiviral drugs.
The molecular basis of the antiviral activity of new and known
drugs and their possible use in chemotherapy of viral disease are
presented in this book."
Biosynthesis of cellular and viral DNA and RNA has been a major
topic in molecular biology and biochemistry. The studies by Arthur
Kornberg and his colleagues on the in-vitro synthesis of DNA have
opened new avenues to understanding the processes controlling the
duplication of the genetic information encoded in the DNA and RNA
of bacterial and mammalian cells. Viral nucleic acids are
replicated in infected cells (bacterial, plant, and animal) by
virus coded enzymes with or without the involvement of proteins and
enzymes coded by the host cells. The ability of the virus to
replicate its genome within a relatively short period in the
infected cell makes it an excellent biological tool for studying
the molecular events in nucleic acid replication. Indeed, the
identification of a number of virus-coded proteins that participate
in the biosynthesis of X174 and SV40 DNA has led to the
construction of in-vitro systems for the study of nucleic acid
biosynthesis. Similarly, studies on the replication of other phage,
animal and plant viruses have provided an insight into the nucleic
acid sequences from which DNA synthesis is initiated, as well as
the proteins and enzymes that regulate the catalyse biosynthetic
processes. Investi gation of the molecular processes involved in
the replication of cellular and mitochondrial genomes has gained
momentum from the rapid developments in the analyses of viral
nucleic acid biosynthesis."
The nucleotide sequence of the gene from which messenger RNA mole
cules are transcribed is in a form that can be translated by
cellular ribosomes into the amino acid sequence of a particular
polypeptide, the product of the gene. The discovery of messenger
RNA more than twenty years ago led to a series of studies on its
organization and function in cells in the presence of infecting
viruses. This volume is devoted to current studies in the field of
cellular and viral messenger RNA. The studies presented provide an
insight into molecular and genetic aspects of messenger RNA.
Special attention was paid by the authors to the molecular
organization of mRNA species, to the processing of mRNA molecules,
and to the different strategies employed by DNA and RNA viruses in
the synthesis of their mRNA. The ability of a virus to take over
the protein-synthesizing mechanisms of an infected cell depends on
its ability to produce mRNA molecules which can affect the host
mRNA or utilize cellular components more efficiently. The
differences between, and similarities of, the strategies of mRNA
synthesis devised by various DNA and RNA viruses are described
herein. This book should be of interest to all students of cellular
and viral genes and scientists in the field. It is suitable as a
textbook for workshops and courses on mRNA. I wish to thank the
authors for their fine contributions and for their interest."
Shortly after the reeognition of the aequired immunodefieieney
syndrome (AIDS) in 1981 (1-3), it was hypothesized that
herpesviruses may play an important role in the etiology or
pathogenesis of this newly identified syndrome (4,5). This theory
was based on the faet that infeetion with herpesviruses was a
prominent elinieal feature in nearly all patients with AIDS (3-5).
Chronie mueocutaneous herpes simplex virus (HSV) infections were
one of the first opportunistie infeetions deseribed in patients
with AIDS (3), and both cytomegalovirus (CMV) and HSV infections
were extremely common in individuals identified to be at highest
risk for aequiring AIDS, such as homosexual men, intravenous drug
users and hemophiliaes (4-8). CMVand Epstein-Barr virus (EBV) were
also prominent infeetions whieh were suspected as possible
etiologic agents of the prolonged fever, wasting, and
Iymphadenopathy that often precedes AIDS, frequently referred to as
the chronie Iymphadenopathy syndrome (9,10). Subsequent elinieal
studies have indeed demonstrated that infeetions with HSV, CMV,
EBV, and even varieella zoster virus (VZV) are frequent
opportunistic infeetions wh ich oeeur among AIDS patients (11-14).
Several of the opportunistie infeetions caused by herpesviruses
include encephalitis, chorioretinitis, hairy leukoplakia,
esophagitis, enteritis, colitis, Burkitt's lymphoma, primary CNS
lymphoma, zoster, and there has even been speculation about the
role of CMV in the pathogenesis of Kaposi's sareoma (15,16).
Furthermore, the herpesviruses, partieularly CMV and EBV have been
known to be strongly associated with immunosuppression,
partieularly of cell-mediated immune functions, which further
supported the hypothesis that herpesviruses may contribute to the
immune defects that eharacterize AIDS."
African swine fever (ASF) is caused by a virus that is classified
as a member of the Iridovirinae family. The disease in the warthog,
the natural host, in Africa was described in 1921 by R. E.
Montgomery. The reservoir of the vi rus is inti cks. The i ntroduct
i on of domestic pi gs into territory occupied by warthogs i nf
ected wi th ASF in the 1960's has endangered the pig industry
around the world. The domestic pig is highly sensitive to ASF and
develops a devastating disease that kills the pig without giving
the immune system a chance to defend the animal against the virus
infection. The ability of ASF virus to infect and destroy cells of
the reticuloendothelial system leaves a defenseless host that
succumbs to an infection which may be described as an acquired
immune deficiency di sease of domestic pi gs. Introduction of the
virus into Iberia in the 1960's led to a series of ASF epidemics in
Spain and Portugal . . and later in France, that caused heavy
economic losses. Between 1976 and 1960, ASF virus made its
appearance in Malta and Sardinia . . as well as in Brazil, The
Dominican Republic . . Haiti, and later in Cuba. In 1985-6 . . ASF
appeared in Belgium and The Netherlands.
This volume in the series Developments in Medical Virology deals
with viruses involved in diabetes mellitus, a syndrome with a
strong genetic background that causes damage to the regulation of
insulin synthesis and function. Viruses were found either to cause
or to stimulate diabetes mellitus in man and in animal models. The
nature of the role of viruses is described by many of the
scientists who participated in the original studies. To complete
the picture, chapters were included that deal with the insulin
gene, the secondary structure of the proinsulin and insulin
receptor polypeptides, pancreatic Langerhans islets, and clinical
considerations of the disease. The aim of Developments in Medical
Virology is to elucidate processes involving viruses as pathogens
of cells and organisms, with special attention to human diseases. A
number of volumes will be devoted to viruses affecting specific
organs (e.g. brain, liver, etc.), while others will elaborate on
the clinical experience in the use of antiviral drugs. The series
is published in parallel with Developments in Molecular Virology,
designed to present an analysis of molecular mechanisms implicated
in virus infection and replicative processes. In addition, the
series Developments in Veterinary Virology provides information on
viruses causing diseases in animals, with special emphasis on
aspects of interest to veterinarians.
The development of recombinant DNA technology has made a marked
impact on molecular virology. The cleavage of viral DNA genomes
with restriction enzymes and the cloning of such DNA fragments in
bacterial p1asmids has led to the amplification of selected viral
DNA fragments for sequencing and gene expression. RNA virus genomes
which can be transcribed to their cDNA form were also cloned in
bacterial p1asmids, facilitating the study of RNA virus genes. With
the elucidation in recent years of the promoter sequence of various
viral genes and the expression of these genes in bacteria or yeast,
the understanding of many viral gene functions has made great
progress. Cloning and expression of viral genes in mammalian cells
was made possible by the construction of shuttle plasmid vectors
which carry the origins of DNA replication from bacteria and/or
mammalian viruses. The expression of viral genes in bacteria, yeast
and eukaryotic cells gives reason to hope that it will be possible
to produce viral antigens in large quantities for use as human or
animal vaccines. The present volume attempts to capture for the
reader some of the high lights of recombinant DNA research in the
field of animal and plant viruses."
Over the generations the skin has been the site for immunization
against smallpox. This method of immunization was described in a
letter written by Lady Mary Montagu on April 1, 1717 in
Adrianopole, Turkey: "The small-pox, so fatal, and so general
amongst us, is here entirely harmless by the invention of
ingrafting, which is the term they give it. . . The old woman comes
with a nut-shell full of the matter of the best sort of small-pox .
. . She immediately rips open (the skin) with a large needle . . .
and puts into the vein as much venom as can lie upon the head of
her needle, and after binds up the wound. There is no example of
anyone that died of it; and you may believe that I am satisfied of
the safety of this experiment since I intend to try it on my dear
little son" (Letters from the right Honourable Lady Mary Montagu
1709-1762. Published by J. M. Dent and Co. London, 2nd edition,
September, 1906, p. 124. ) The "variolation" method was, 80 years
later, markedly improved by the use of cowpox virus, as reported by
Edward Jenner in 1796. The successful method of intradermal
immunization against smallpox and later against other virus
diseases is in fact based on the presence of anitigen-presenting
dendritic cells in the skin.
Shortly after the reeognition of the aequired immunodefieieney
syndrome (AIDS) in 1981 (1-3), it was hypothesized that
herpesviruses may play an important role in the etiology or
pathogenesis of this newly identified syndrome (4,5). This theory
was based on the faet that infeetion with herpesviruses was a
prominent elinieal feature in nearly all patients with AIDS (3-5).
Chronie mueocutaneous herpes simplex virus (HSV) infections were
one of the first opportunistie infeetions deseribed in patients
with AIDS (3), and both cytomegalovirus (CMV) and HSV infections
were extremely common in individuals identified to be at highest
risk for aequiring AIDS, such as homosexual men, intravenous drug
users and hemophiliaes (4-8). CMVand Epstein-Barr virus (EBV) were
also prominent infeetions whieh were suspected as possible
etiologic agents of the prolonged fever, wasting, and
Iymphadenopathy that often precedes AIDS, frequently referred to as
the chronie Iymphadenopathy syndrome (9,10). Subsequent elinieal
studies have indeed demonstrated that infeetions with HSV, CMV,
EBV, and even varieella zoster virus (VZV) are frequent
opportunistic infeetions wh ich oeeur among AIDS patients (11-14).
Several of the opportunistie infeetions caused by herpesviruses
include encephalitis, chorioretinitis, hairy leukoplakia,
esophagitis, enteritis, colitis, Burkitt's lymphoma, primary CNS
lymphoma, zoster, and there has even been speculation about the
role of CMV in the pathogenesis of Kaposi's sareoma (15,16).
Furthermore, the herpesviruses, partieularly CMV and EBV have been
known to be strongly associated with immunosuppression,
partieularly of cell-mediated immune functions, which further
supported the hypothesis that herpesviruses may contribute to the
immune defects that eharacterize AIDS."
This volume in the series Developments in Medical Virology deals
with viruses involved in diabetes mellitus, a syndrome with a
strong genetic background that causes damage to the regulation of
insulin synthesis and function. Viruses were found either to cause
or to stimulate diabetes mellitus in man and in animal models. The
nature of the role of viruses is described by many of the
scientists who participated in the original studies. To complete
the picture, chapters were included that deal with the insulin
gene, the secondary structure of the proinsulin and insulin
receptor polypeptides, pancreatic Langerhans islets, and clinical
considerations of the disease. The aim of Developments in Medical
Virology is to elucidate processes involving viruses as pathogens
of cells and organisms, with special attention to human diseases. A
number of volumes will be devoted to viruses affecting specific
organs (e.g. brain, liver, etc.), while others will elaborate on
the clinical experience in the use of antiviral drugs. The series
is published in parallel with Developments in Molecular Virology,
designed to present an analysis of molecular mechanisms implicated
in virus infection and replicative processes. In addition, the
series Developments in Veterinary Virology provides information on
viruses causing diseases in animals, with special emphasis on
aspects of interest to veterinarians.
The nucleotide sequence of the gene from which messenger RNA mole
cules are transcribed is in a form that can be translated by
cellular ribosomes into the amino acid sequence of a particular
polypeptide, the product of the gene. The discovery of messenger
RNA more than twenty years ago led to a series of studies on its
organization and function in cells in the presence of infecting
viruses. This volume is devoted to current studies in the field of
cellular and viral messenger RNA. The studies presented provide an
insight into molecular and genetic aspects of messenger RNA.
Special attention was paid by the authors to the molecular
organization of mRNA species, to the processing of mRNA molecules,
and to the different strategies employed by DNA and RNA viruses in
the synthesis of their mRNA. The ability of a virus to take over
the protein-synthesizing mechanisms of an infected cell depends on
its ability to produce mRNA molecules which can affect the host
mRNA or utilize cellular components more efficiently. The
differences between, and similarities of, the strategies of mRNA
synthesis devised by various DNA and RNA viruses are described
herein. This book should be of interest to all students of cellular
and viral genes and scientists in the field. It is suitable as a
textbook for workshops and courses on mRNA. I wish to thank the
authors for their fine contributions and for their interest."
The development of recombinant DNA technology has made a marked
impact on molecular virology. The cleavage of viral DNA genomes
with restriction enzymes and the cloning of such DNA fragments in
bacterial p1asmids has led to the amplification of selected viral
DNA fragments for sequencing and gene expression. RNA virus genomes
which can be transcribed to their cDNA form were also cloned in
bacterial p1asmids, facilitating the study of RNA virus genes. With
the elucidation in recent years of the promoter sequence of various
viral genes and the expression of these genes in bacteria or yeast,
the understanding of many viral gene functions has made great
progress. Cloning and expression of viral genes in mammalian cells
was made possible by the construction of shuttle plasmid vectors
which carry the origins of DNA replication from bacteria and/or
mammalian viruses. The expression of viral genes in bacteria, yeast
and eukaryotic cells gives reason to hope that it will be possible
to produce viral antigens in large quantities for use as human or
animal vaccines. The present volume attempts to capture for the
reader some of the high lights of recombinant DNA research in the
field of animal and plant viruses."
Research on antiviral drugs and their mode of action in infected
cells. in animals and in man. has led to a better understanding of
the molecular pro cesses involved in virus replication. Screeninq
of large numbers of natural and semisynthetic compounds resulted in
the characterization of certain sub stances that had a limited
efficiency as antiviral druqs. A few chemically synthesized
compounds were also found to be effective as antiviral agents in
the chemotherapy of human virus diseases. A major difficulty in the
develop ment of effective antiviral agents has been the lack of
selectivity. and toxicity for uninfected cells. of drugs that
effectively inhibited virus replication in vitro. Further
understanding of the molecular processes of virus replication in
infected cells has resulted in the development of new antivirals
directed at virus-coded enzymes or proteins. Recent studies on
antivirals that are activated by the herpes simplex virus type
l-coded thy midine kinase from a prod rug to an antiviral drug have
opened new directions in the development of effective antiviral
drugs. The present book deals with a number of antiviral drugs
effective against herpes simplex viruses and provides some insight
into the molecular aspects of virus replication. It also throws
light on the new approaches to the development of antiviral drugs.
The molecular basis of the antiviral activity of new and known
drugs and their possible use in chemotherapy of viral disease are
presented in this book."
Biosynthesis of cellular and viral DNA and RNA has been a major
topic in molecular biology and biochemistry. The studies by Arthur
Kornberg and his colleagues on the in-vitro synthesis of DNA have
opened new avenues to understanding the processes controlling the
duplication of the genetic information encoded in the DNA and RNA
of bacterial and mammalian cells. Viral nucleic acids are
replicated in infected cells (bacterial, plant, and animal) by
virus coded enzymes with or without the involvement of proteins and
enzymes coded by the host cells. The ability of the virus to
replicate its genome within a relatively short period in the
infected cell makes it an excellent biological tool for studying
the molecular events in nucleic acid replication. Indeed, the
identification of a number of virus-coded proteins that participate
in the biosynthesis of X174 and SV40 DNA has led to the
construction of in-vitro systems for the study of nucleic acid
biosynthesis. Similarly, studies on the replication of other phage,
animal and plant viruses have provided an insight into the nucleic
acid sequences from which DNA synthesis is initiated, as well as
the proteins and enzymes that regulate the catalyse biosynthetic
processes. Investi gation of the molecular processes involved in
the replication of cellular and mitochondrial genomes has gained
momentum from the rapid developments in the analyses of viral
nucleic acid biosynthesis."
This book was written during a period when the technologies of
genetic engineering were being applied to the study of animal
viruses and when the organization and function of individual virus
genes were being elucidated. This book, which uses human and animal
viruses as models, aims to under stand the developments in
molecular virology during the last 20 years. Al though molecular
virology could also be taught by means of bacteriophages or plant
viruses, the advantage of using animal viruses is in their ability
to cause human and animal diseases as well as to transform cells, a
primary problem in medicine. For the sake of clarity and
convenience, not all the individual contributors to the various
aspects of molecular virology were cited in the text. Instead, the
reader is referred to review articles or key papers that list the
numerous excel lent publications that have contributed to
clarification of the various molecular processes. Thus the
end-of-chapter bibliographies will guide the reader to the
publications in which the original contributing authors are quoted.
References given under the heading Recommended Reading are intended
to assist those interested in pursuing a given subject further. I
hope that this book will fulfill the purpose for which it is
designed, and I urge readers to contact me if errors are found or
updating is required."
Herpesviruses, classified in the family Herpesviridae, are
important human and animal pathogens that can cause primary, latent
or recurrent infections and even cancer. The major interest in
research on herpesviruses today focuses on understanding the
organization of the DNA genome, as well as on characterizing the
viral genes in regard to their control and function. Modern
techniques have allowed the viral DNA to become a molecular tool in
the study of gene function, since it is now possible to implant the
DNA into eukaryotic cells. This book contains original studies on
the structure and organization of the DNA of human and animal
herpes viruses. The various chapters acquaint the reader with the
organization of the viral DNA, the mRNA transcripts, the
replicative intermediates of the viral DNA, defective DNA genomes
and their mode of synthesis, analyses of the viral DNA sequences in
transformed cells, and the relationship between the presence of
viral DNA fragments in the cancer cells and the transformed state
of the cells."
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