Epstein–Barr Virus
http://www.100md.com
《新英格兰医药杂志》
On March 22, 1961, Denis Burkitt, a self-described "bush surgeon" working at Mulago Hospital in Kampala, Uganda, delivered a lecture at Middlesex Hospital Medical School in London entitled "The Commonest Children's Cancer in Tropical Africa — A Hitherto Unrecognised Syndrome." In the audience, captivated, was M. Anthony Epstein, a pathologist and accomplished electron microscopist. And the rest, as they say, is history. In December 1963, biopsies from Kampala arrived at Epstein's laboratory, where some of the tumor cells grew quickly in culture. On February 24, 1964, Epstein first saw in cultured lymphoma cells the herpesvirus that came to bear his name and that of his colleague Yvonne Barr. Unable to evoke the interest of local virologists, Epstein sent two cell lines to Werner and Gertrude Henle at the Children's Hospital of Philadelphia. The Henles had spent years studying persistent viral infections in cell cultures. Using immunofluoresence, they identified viral capsid antigens, which are products of the virus lytic cycle, in some of the cultured cells (see photomicrograph).
Photomicrograph Showing Cultured Lymphoid Cells That Express Epstein–Barr Viral Capsid Antigens.
Courtesy of the Centers for Disease Control and Prevention/Dr. Paul M. Feorino.
These antigens served as the basis for seroepidemiologic studies. The Henles, searching for an illness caused by the newly discovered virus, screened human serum samples for antibodies to viral capsid antigens. One answer came quite unexpectedly in August 1967, when a technician in their laboratory became ill with infectious mononucleosis. The Henles, who had providently saved the serum sample collected from the technician before her illness, discovered that antibodies to viral capsid antigens developed after her illness. Her blood lymphocytes grew into a continuous cell line that contained these antigens.
The seroepidemiologic approach implicated Epstein–Barr virus (EBV) in several cancers. Elevated titers of antibodies to capsid antigen preceded the development of Burkitt's lymphoma and Hodgkin's disease, often by several years. Elevated IgA antibodies to EBV lytic-cycle antigens were found in patients with nasopharyngeal cancer. These serologic findings were soon complemented by molecular diagnostics. EBV DNA and EBV-encoded RNAs were identified in tumors. The tumors were found to be monoclonal with respect to EBV infection and cellular changes, such as immunoglobulin gene rearrangements. EBV was shown to immortalize human B lymphocytes with high efficiency, and the virus induced lymphomas in nonhuman primates.
EBV became the most intensively studied human cancer virus. Epstein–Barr Virus is the first book devoted to an in-depth exploration of the molecular biology and immunology of the virus–host interaction. Editor Erle Robertson and his contributors, an all-star team of pioneers and scholars, address the intricate details of the lifestyles of this ancient virus, whose relatives span all of primate evolution, including New and Old World monkeys and great apes. The intensive research on EBV summarized in this book focuses on seminal questions: How does the virus immortalize lymphocytes? Does the virus contribute to invasion and metastasis as well as altering cell growth? How does the viral genome persist within the cell and for the lifetime of infected individuals? How does the virus switch from a latent state of limited gene expression to lytic replication? How does the gene expression program of the virus differ among various diseases associated with EBV?
Research on the mechanisms of pathogenesis of EBV came of age during a time of dramatic advances in molecular and cellular biology. The entire genome of one EBV strain was completely sequenced in 1984. The methods developed to accomplish this feat were the foundation of the revolution in genomics. The availability of the DNA sequence led to an exquisitely detailed understanding of how the viral genome is organized and what are the patterns of gene expression; it also enabled researchers to dissect the function of many key viral genes. A recurrent lesson of the book is that the virus parasitizes every cell system: signal transduction, cell-cycle control, regulation of gene expression, posttranscriptional RNA processing, protein modification and stability, and DNA replication. In our era, when novel functions of RNA are being explored and exploited, it is notable that EBV invariably expresses two small abundant noncoding RNAs (the EBV-encoded RNAs), as well as larger noncoding RNAs and many micro RNAs discovered very recently.
The human immune system has undoubtedly been shaped by its coevolution with EBV and its ancestors. Every component of humoral, innate, and adaptive immunity is brought to bear on the virus and virally infected cells. The virus, in turn, uses a wide array of strategies to evade immune recognition. The thesis of McFarland Burnet and Lewis Thomas that cancer is controlled by immunosurveillance has, as one of its clearest exemplars, B-cell lymphoproliferative diseases that occur in immunodeficient individuals infected with EBV. The virus may induce autoimmunity by immortalizing clones of B cells that produce autoantibodies or by activating endogenous retroviruses that encode superantigens. B cells are major targets of infection. Patterns of viral gene expression differ in naive, germinal-center and memory B cells. B-cell lymphomas associated with the virus reflect different B-cell lineages.
Where has all this research led in terms of the prevention or treatment of cancers associated with EBV? T-cell immunotherapy for EBV-associated lymphoproliferative disease in recipients of solid-organ or allogeneic stem-cell transplants is one exciting translational application. Prospective screening for high-antibody titers to detect EBV-associated tumors and the ability to produce human monoclonal antibodies are also important practical outcomes. The results of basic research are also impressive; studies of EBV have elucidated antigen-processing pathways and novel lineages of memory B cells.
This book describes basic research on the virus and strongly emphasizes the functions of viral genes expressed in tumors. In an elegant summation, Alan Rickinson poses questions about tumorigenicity that are fodder for future generations and call for taking the problems directly back to patients: Why is only a subgroup of some tumors (e.g., Hodgkin's disease) positive for EBV? Why does the tumorigenicity of the virus show such striking geographic patterns (e.g., nasopharyngeal cancer in southern China)? How do virally induced and cellular alterations (e.g., the translocation of the c-myc oncogene in Burkitt's lymphoma) interact?
In his preface, Robertson states that his objective was to "provide novices to the field a cohesive blueprint which represented the body of work in EBV." We are all novices when it comes to understanding this compelling, beautiful, and complex virus and its interactions with human beings. This is a book to have at hand, whether one is uninitiated or has studied the virus for a lifetime.
George Miller, M.D.
Yale University School of Medicine
New Haven, CT 06520
george.miller@yale.edu(Edited by Erle S. Roberts)
Photomicrograph Showing Cultured Lymphoid Cells That Express Epstein–Barr Viral Capsid Antigens.
Courtesy of the Centers for Disease Control and Prevention/Dr. Paul M. Feorino.
These antigens served as the basis for seroepidemiologic studies. The Henles, searching for an illness caused by the newly discovered virus, screened human serum samples for antibodies to viral capsid antigens. One answer came quite unexpectedly in August 1967, when a technician in their laboratory became ill with infectious mononucleosis. The Henles, who had providently saved the serum sample collected from the technician before her illness, discovered that antibodies to viral capsid antigens developed after her illness. Her blood lymphocytes grew into a continuous cell line that contained these antigens.
The seroepidemiologic approach implicated Epstein–Barr virus (EBV) in several cancers. Elevated titers of antibodies to capsid antigen preceded the development of Burkitt's lymphoma and Hodgkin's disease, often by several years. Elevated IgA antibodies to EBV lytic-cycle antigens were found in patients with nasopharyngeal cancer. These serologic findings were soon complemented by molecular diagnostics. EBV DNA and EBV-encoded RNAs were identified in tumors. The tumors were found to be monoclonal with respect to EBV infection and cellular changes, such as immunoglobulin gene rearrangements. EBV was shown to immortalize human B lymphocytes with high efficiency, and the virus induced lymphomas in nonhuman primates.
EBV became the most intensively studied human cancer virus. Epstein–Barr Virus is the first book devoted to an in-depth exploration of the molecular biology and immunology of the virus–host interaction. Editor Erle Robertson and his contributors, an all-star team of pioneers and scholars, address the intricate details of the lifestyles of this ancient virus, whose relatives span all of primate evolution, including New and Old World monkeys and great apes. The intensive research on EBV summarized in this book focuses on seminal questions: How does the virus immortalize lymphocytes? Does the virus contribute to invasion and metastasis as well as altering cell growth? How does the viral genome persist within the cell and for the lifetime of infected individuals? How does the virus switch from a latent state of limited gene expression to lytic replication? How does the gene expression program of the virus differ among various diseases associated with EBV?
Research on the mechanisms of pathogenesis of EBV came of age during a time of dramatic advances in molecular and cellular biology. The entire genome of one EBV strain was completely sequenced in 1984. The methods developed to accomplish this feat were the foundation of the revolution in genomics. The availability of the DNA sequence led to an exquisitely detailed understanding of how the viral genome is organized and what are the patterns of gene expression; it also enabled researchers to dissect the function of many key viral genes. A recurrent lesson of the book is that the virus parasitizes every cell system: signal transduction, cell-cycle control, regulation of gene expression, posttranscriptional RNA processing, protein modification and stability, and DNA replication. In our era, when novel functions of RNA are being explored and exploited, it is notable that EBV invariably expresses two small abundant noncoding RNAs (the EBV-encoded RNAs), as well as larger noncoding RNAs and many micro RNAs discovered very recently.
The human immune system has undoubtedly been shaped by its coevolution with EBV and its ancestors. Every component of humoral, innate, and adaptive immunity is brought to bear on the virus and virally infected cells. The virus, in turn, uses a wide array of strategies to evade immune recognition. The thesis of McFarland Burnet and Lewis Thomas that cancer is controlled by immunosurveillance has, as one of its clearest exemplars, B-cell lymphoproliferative diseases that occur in immunodeficient individuals infected with EBV. The virus may induce autoimmunity by immortalizing clones of B cells that produce autoantibodies or by activating endogenous retroviruses that encode superantigens. B cells are major targets of infection. Patterns of viral gene expression differ in naive, germinal-center and memory B cells. B-cell lymphomas associated with the virus reflect different B-cell lineages.
Where has all this research led in terms of the prevention or treatment of cancers associated with EBV? T-cell immunotherapy for EBV-associated lymphoproliferative disease in recipients of solid-organ or allogeneic stem-cell transplants is one exciting translational application. Prospective screening for high-antibody titers to detect EBV-associated tumors and the ability to produce human monoclonal antibodies are also important practical outcomes. The results of basic research are also impressive; studies of EBV have elucidated antigen-processing pathways and novel lineages of memory B cells.
This book describes basic research on the virus and strongly emphasizes the functions of viral genes expressed in tumors. In an elegant summation, Alan Rickinson poses questions about tumorigenicity that are fodder for future generations and call for taking the problems directly back to patients: Why is only a subgroup of some tumors (e.g., Hodgkin's disease) positive for EBV? Why does the tumorigenicity of the virus show such striking geographic patterns (e.g., nasopharyngeal cancer in southern China)? How do virally induced and cellular alterations (e.g., the translocation of the c-myc oncogene in Burkitt's lymphoma) interact?
In his preface, Robertson states that his objective was to "provide novices to the field a cohesive blueprint which represented the body of work in EBV." We are all novices when it comes to understanding this compelling, beautiful, and complex virus and its interactions with human beings. This is a book to have at hand, whether one is uninitiated or has studied the virus for a lifetime.
George Miller, M.D.
Yale University School of Medicine
New Haven, CT 06520
george.miller@yale.edu(Edited by Erle S. Roberts)