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."