The forerunner to this book was published nearly 15 years ago as part of a Cold Spring Harbor Laboratory series on the molecular biology of tumor viruses. That series—first a single volume covering both DNA and RNA tumor viruses in 1973, then books that separately addressed DNA and RNA tumor viruses in 1980 and 1982—was a response to a profound change in the study of viruses that cause cancer in experimental animals. Since the first decade of this century, veterinary pathologists and virologists have described many kinds of tumors that arise in birds, rodents, ungulates, cats, and primates after infection by a variety of viruses. Beginning in the late 1960s, this descriptive science became more analytic, as new tools—genetics and molecular and cellular biology—allowed investigators to address the mechanisms by which such viruses grow and dramatically alter cell behavior. This new approach to tumor viruses—centered around the oncogenic and replicative capacities of several classes of DNA viruses and one class of RNA viruses, the retroviruses—was the focus of the earlier volumes in this series.

By 1982, when the predecessor of this book appeared, it was still possible to describe virtually all of the salient features of the retroviruses in a single (albeit heavy) volume. That volume included a complete catalog of wild-type and mutant retroviruses and descriptions of many viral genes and proteins, with special emphasis on viral oncogenes and their progenitor proto-oncogenes in host genomes. The book also provided an account of the central events in the retroviral life cycle, the maps of several retroviral genomes, and the full sequences of a few. Progress was occurring at such a rapid pace, however, that when a paperback edition with supplementary information was issued just three years later, two volumes were required to display the profusion of new maps and nucleotide sequences and to describe extraordinary developments in human retrovirology, especially the isolation of human immunodeficiency viruses types 1 and 2 (HIV-1 and HIV-2) and the identification of these viruses as the cause of acquired immunodeficiency syndrome (AIDS).

The intellectual context in which we have assembled the current book is substantially different from that in which the earlier one was written. Fifteen years ago, the drive to study retroviruses was rooted principally in the traditional goal of using animal models to understand human cancer. The historical importance of retroviruses in the discovery of cancer genes is now widely appreciated, but many of the recent spectacular revelations about the molecular basis of cancer have occurred in other venues—such as human genetics, cell signaling, and developmental biology—rather than virology. Instead, the central goals of retrovirology today are the treatment and the prevention of AIDS and the use of retroviruses as gene delivery devices. These goals have only intensified the need to further dissect viral particles and genomes, understand their modes of replication, and describe host responses to infection. Such efforts have focused on structural properties of viral proteins and their assembly; host receptors for retroviruses and their interactions with envelope proteins; the mechanism of proviral integration; the regulation of viral gene expression; and various aspects of pathogenesis and the immune response to retroviral infection.

Not surprisingly, recent efforts to examine these issues have focused largely on the HIVs and the retroviruses most commonly used to create vectors, the murine leukemia viruses (MLVs). It is our contention, and an assumption on which this book is built, that a full understanding of any single retrovirus depends on an appreciation of the common properties of retroviruses as a class, as well as the unique features of each type. For many investigators recently recruited to this discipline through an interest in AIDS or gene therapy, the relevance of chicken or feline viruses to the matter at hand may seem remote, and the prospect of acquiring a broad view of a field with so many virus isolates may seem daunting. In hopes of attenuating such concerns, we have organized the current volume much like the last, by topic rather than by virus, so that the similarities and differences among retroviruses can be illuminated in the context of specific functions. Because current understanding of the virus life cycle is so much improved, separate chapters are devoted to virus entry, reverse transcription, integration, transcription, and translation and maturation, topics that could be addressed largely within a single chapter 15 years ago. The intervening years have brought the identification of several host-encoded receptors for retroviruses; the deciphering of three-dimensional structures of the three major retroviral enzymes (reverse transcriptase, integrase, and protease) and of the major virion structural proteins and the components of the envelope glycoprotein. The mechanism of proviral integration is now clear. A better understanding of animal cells—transcription and translation, the cell cycle, membrane fusion, general recombination and specialized transposition, RNA processing, and the immune response—has affected our thinking about retroviruses in ways that have been incorporated into relevant chapters. We have also placed greater emphasis on viral pathogenesis, especially the events that follow infection by HIV, on efforts to counter HIV with antiviral drugs or immune-based strategies, and on the practical aspects of using viruses to deliver genes to animals or human subjects.

The book is divided into two parts. The first deals primarily with viral structure, function, and replication; the second with the interplay between the virus and the host, focusing primarily on the effects of the virus on the host. This division, which is not intended to be rigid or absolute, is marked by a short insertion or “Intermezzo” between Chapters 7 and 8. This small section is provided to help the reader apply the lessons learned about the viral life cycle, discussed in the first part of the book, to the larger context of the virus and its host, the subject of the second part of the book.

Although it is not possible to understand any aspect of retroviruses, or the retroviral life cycle, in isolation, the chapters are intended to be sufficiently complete to be read independently in any order. There is, at the beginning of each chapter, a brief introduction that is intended to place the information presented in the chapter in its proper context. Although we wanted each chapter to be individually accessible, we also tried to avoid significant overlap between the chapters, choosing instead, where appropriate, to refer the reader to complementary material found elsewhere in the book.

Improvements in storage and retrieval of scientific information have reduced the need to provide details about viral sequences, maps, and structures on paper. Instead, we have supplied accession numbers that can be used to obtain information from the databases, accompanied by diagrams and discussions showing how this information can be used most productively. Unfortunately, the available sequence databases do not usually have the complete sequences of retroviral genomes in a standard format, nor is there, in most cases, relevant information in the databases accurately delineating gene boundaries, readthrough sites and rules, protein processing information, and so forth. We have provided this information in Appendix 2, in a standard format, for a series of retroviral genomes representing prototypes of the major families of retroviruses. To facilitate the use of this information, we have created corresponding entries in the Genbank sequence database; the accession numbers are given in the Appendix.

Happily, the CSHL Press has been willing to make greater use of color plates in the current volume, allowing us to show protein structures, molecular mechanisms, and other elements in arresting and informative illustrations.

This book, like many such ventures, has been in preparation for longer than any of us would have hoped at the outset. Much of the credit for getting the task completed is due to the many authors who contributed chapters; the colleagues who helped our authors include recent and sometimes unpublished information. We also wish to thank Wayne Chen and the artists from Graphic Visions Associates; Richard Frederickson for the cover design; and Mary Bostic-Fitzgerald and Hilda Marusiodis for assistance with manuscript preparation. We are particularly grateful to the staff of the Cold Spring Harbor Laboratory Press, especially Nancy Ford, Dorothy Brown, and Joan Ebert, who have kept faith with our now ancient agreement to make this book.

J.M. Coffin

S.H. Hughes

H.E. Varmus