This article is concerned with the use of viral models for the study of the mechanism of protein biosynthesis and its regulation. The scope is restricted mainly to general aspects of animal viral systems and how these systems may be used to approach the question of cellular regulation. Most information on the regulation of metabolic processes in eukaryotic cells comes from the study of bacteria and from the successful application of this knowledge to higher systems. However, differences in regulation of the translation of genetic information from the messenger RNA into protein may be expected between prokaryotes and eukaryotes. Due to the short half-life of prokaryotic mRNAs, transcription has been considered as the main mechanism controlling gene expression. Nevertheless, during recent years firm evidence has been accumulated for additional regu latory factors operating during translation. This topic was recently reviewed by HASELKORN and ROTHMAN-DENES (1973) and by KOZAK and NATHANS (1972)."

"When we give a definition it is for the purpose of using it." HENRI POINCARE in Science and Method A. Objectives The first version of this paper was written to introduce new students and fellows of my laboratory to the mysteries of herpesviruses. Consonant with this design sections dealing with well documented data were trimmed to the bone whereas many obscure phenomena, controversial data and seemingly trivial observations were discussed generously and at length. There is some doubt as to whether it was meant to be published, but it was not a review. The objective of reviews is frequently to bring order. But alas, even the most fluent summation of credible data frequently makes dull reading and too much plausible order, like very little entropy in chemical reactions, is not the most suitable environment on which to nurture the urge to discover. This version is more charitable but not less inbalanced. The bibliography reflects the intent of the paper and was updated last in December of 1968. It should be obvious without saying that no single account such as this can do justice or injustice, as the case may be, to the several hundred papers published on herpesviruses each year or to the many thousand papers published on herpesviruses since the first of the members of the family was experimentally transmitted to a heterologous host more than half a century ago (GRUTER, 1924). B. Definition 1.

The study of streptococcal infections and their sequelae has in the last two decades yielded several important findings on the biological properties of cellular and extracellular products of group A streptococci. These findings have contributed to a better knowledge of the pathological reactions occurring in the macroorganism during host-parasite interactions. Nevertheless, the pathogenesis of streptococcal infections is not fully understood. So far there has been no success in eliciting experimentally, either through the action of the substances isolated from the cell, or from broth culture filtrate of group A streptococci, symptoms that are fully identical with any type of acute streptococcal infection. It also has not been possible to explain the mUltiplicity of clinical and histological changes caused by streptococci as being due solely to anyone of these substances or a combination thereof. The same applies to the sequelae of streptococcal infections, rheumatic fever and acute glomerulonephritis. We do not know how the group A strepto coccus elicits these diseases and we have only a partial understanding of the pathological processes, initiated by this streptococcus, and resulting in cardiac or renal lesions. It is clear that an organism infected by streptococci is exposed to the action of a complex of substances. A more detailed recognition of the biological activity of the single components and their combination under defined experimental conditions may be capable, it is hoped, to explain the pathologic processes triggered in the course. of the development of group A streptococcal infection."

Several discoveries are noteworthy for allowing us to probe the recesses of the virus infected cell and to search for cryptic viral genomes which might provide clues in our studies of cancer etiology or developmental biology. One of the most notable was the dis covery of reverse transcriptase. This marked a momentous occasion in the history of molecular biology. Not only did it provide insight into the mechanism of persistence of retroviruses but it also provided us with an enzyme that could synthesize a DNA copy of any RNA. This DNA copy could then be used as a hybridization reagent to search for both complementary DNA and viral-specific RNA. Thus one could follow the course of any viral infection or probe in tumor cells for hidden viral genomes. Second, a great deal of credit must be given to the geneticists who isolated the various deletion mutants in the 'avian retrovirus system and thus provided us with the frrst means of isolating gene-spe cific probes. Finally, the laboratories which have mapped the genome have provided us with the framework in which to ask very specific questions with our gene-specific probes. Recently, numerous excellent reviews concerning various aspects of the retroviruses have appeared. In this review I shall not even attempt to present a comprehensive review of retroviruses."

At the end of the last century and the beginning of this century, the prob lems of immunity in lower vertebrates and the influence of environmental temperature attracted attention for the first time (ERNST, 1890; WIDAL and SICARD, 1897; METCHNIKOFF, 1901). However, relatively little work has been done on this subject until recently. The early investigators were chiefly in terested in the immuno-pathological problems. They immunized various species of lower vertebrates essentially with bacterial vaccines; agglutinating, neutralizing and protective antibodies were detected in their blood. The in fluence of environmental temperature on the immune response was investigated, since this subject represented great economical and theoretical importance. Epizootic diseases were observed to occur in relation to the cold season of the year, when the decrease or spontaneous increase of water temperature occurred (SCHAPERCLAUS, 1965; BESSE et al. , 1965; KLONTZ et al. , 1965 WOOD,1966). The immunological deficiency of fish, caused by their natural or experimental stay in cold water, is now evident for both humoral and cellular immunity. In this review we will focus on two points: We shall attempt (1) to explain the mechanism by which the environmental temperature influences the immune resistance of fish to pathogens, (2) to determine the chronological location of this temperature-sensitive stage in the process of antibody formation, and to make some approaches to the general antibody formation mechanism.

Interest in the general field of tumor immunology has grown phenomenally in recent years. The number of publications con tinues to grow in seemingly exponential fashion and the end is not yet in sight. Under these conditions, it is very difficult for any individual investigator to perceive the whole, or even the small portion within which his own efforts must necessarily be confined. Weare thus very fortunate when an investigator with long and wide experience in the field of tumor immunology takes the time to share his perspectives of a portion of that field. Dr. Koldovsky has been one of the pioneers in tumor immunology and he con tinues to contribute, especially in the area of CEA. In the present survey he has reviewed the status of CEA, setting forth not only the literature, but his own interpretation of that literature. For this endeavor, all workers in tumor immunology will be truely grateful."

This volume is dedicated to the memory of the late Professor WERNER BRAUN, one of the most devoted and active members of the Editorial Board of the Current Topics in Microbiology and Immunology, who passed away, after suffering a heart attack, in November 1972. Dr. WERNER BRAUN was born in Berlin, Germany, on November 16,1914. During his highschool days in Berlin he did research work on problems of genetics as a young guest in the Kaiser-Wilhelm-Institut fur Biologie, in the department of Prof. R. GOLDSCHMIDT. I remember his colourful description of his discussions during this period, while still a teen-ager, with OTTO WAR- BURG. He studied biology and medicine at the University of G6ttingen and received a Ph.D. degree in biology in 1936. In the same year he left Nazi Germany and came to the United States first as a Guest Investigator in Genetics at the University of Michigan at Ann Arbor, and then in Berkeley, where he carried out his work in the Depart- ments of Zoology and of Veterinary Science until 1948. He was engaged during this period in the study of problems concerned with physiological genetics, bacterial variation, immunology and biochemistry.

The expression of many bacterial genes adapts itself in an almost in stantaneous and reversible way to specific environmental changes. More specifically, the concentration of a number of metabolites, a function of the amounts of enzymes involved in their synthesis or degradation, in turn retroacts on the rate of synthesis of these enzymes. The genetic bases for this regulation were established by JACOB and MONOD (1961). These authors also showed how the known elements of these regulatory mechanisms could be connected into a wide variety of circuits endowed with any desired degree of stability, in order to account for essentially irreversible processes like differentiation (MONOD and JACOB, 1961). The general principles used by JACOB and MONOD in their study of negative regulation were extended to positive regulation by ENGLESBERG et al. (1965). An independent approach permitted the discovery of positive controls in temperate bacteriophages (see below, III). Each control operation is mediated by a pair of complementary genetic elements (hereafter called "control cell"): a control gene which produces a l control (or regulator) protein and a control site which is the target for the regulator protein. Negative control means that the control protein (repressor) prevents gene expression. One deals with positive control when the control protein (activator) is necessary for this expression. It has become apparent that, as initially postulated by JACOB and MONOD, control of gene expression operates, at least to a large extent, at the transcriptional level.

The study of the genetic regulation of immune response to natural multidetermi nant immunogens was undertaken by the method of bidirectional selective breed ing of High or Low antibody responder lines of mice. Five Selections are described: Selection I, carried out for agglutinin responsiveness to sheep erythrocytes and pigeon erythrocytes alternated in each generation. Selection II, carried out for agglutinin responsiveness to sheep erythrocytes repeated in each generation. Selection III and Selection IV performed respectively for agglutinin response to flagellar or somatic antigens of Salmonella typhimurium and Salmonella oranienburg alternated in each generation. Selection V, performed for passive agglutinin response to bovine serum albumin and rabbit gamma globulin alternated in each generation. In each Selection the character investigated is polygenic. High and Low responder lines diverge progressively during the selective breeding. The maximal interline separation (selection limit) is reached in the 7th-16th generations. High and Low responder lines at selection limit are considered homozygous for the character submitted to se ection. Their variance is therefore only due to environ mental effects. The difference in agglutinin titre between High and Low lines is 220-fold in Selection I, 103-fold in Selection II, 90-fold in Selection III, 85-fold in Selection IV and 275-fold in Selection V. The partition of genetic and environmental variances in the foundation popu lations of the five Selections is established. The proportion of genetic variance is 60% in Selection I; 49% in Selection II; 51% in Selection III; 47% in Selection IV and 76% in Selection V."

Phenomena as diverse as tuberculin sensitivity, delayed sensitivity to soluble proteins other than tuberculin, contact allergy, homograft rejection, experimental autoallergies, and the response to many microorganisms, have been classified as members of the class of immune reactions known as delayed or cellular hypersensitivity. Similarities in time course, histology, and absence of detectable circulating immunoglobulins characterize these cell-mediated immune reactions in vivo. The state of delayed or cellular hypersensitivity can be transferred from one animal to another by means of sensitized living lymphoid cells (CHASE, 1945; LANDSTEINER and CHASE, 1942; MITCHISON, 1954). The responsible cell has been described by GOWANS (1965) as a small lymphocyte. Passive transfer has also been achieved in the human with extracts of sensitized cells (LAWRENCE, 1959). The in vivo characteristic of delayed hypersensitivity from which the class derives its name is the delayed skin reaction. When an antigen is injected intradermally into a previously immunized animal, the typical delayed reaction begins to appear after 4 hours, reaches a peak at 24 hours, and fades after 48 hours. It is grossly characterized by induration, erythyma, and occasionally necrosis. The histology of the delayed reaction has been studied by numerous investigators (COHEN et al. , 1967; GELL and HINDE, 1951; KOSUNEN, 1966; KOSUNEN et al. , 1963; MCCLUSKEY et al. , 1963; WAKSMAN, 1960; WAKSMAN, 1962). Initially dilatation of the capillaries with exudation of fluid and cells occurs.

The processes involved in herpesvirus replication, latency, and oncogenic transformation, have, in general, been rather poorly defined. A primary reason for this is the size and complexity of the herpesvirus genome. Undoubtedly, a better understanding of the functions of the viral genome in infected and transformed cells will be achieved through studies with temperature-sensitive (ts) mutants of herpesviruses since, theoretically, any essential gene function can be affected by mutants of this type. A. The Herpesviruses A consideration of the genetic analysis of members of the herpesvirus group necessitates a description, albeit brief, of the properties of the group and, most importantly, of their genetic material. The herpesviruses comprise a group of relatively large (100-150 nm), enveloped viruses. The envelope surrounds an icosahedral capsid enclosing a core which contains double stranded DNA (ROIZMAN, 1969). The group is thus defined on the basis of a common virion morphology. In addition to a common structure, members of the group share a number of biological properties such as a similar replicative cycle, the ability to cause latent and chronic infections, and the ability to induce antigenic modifications of infected cell membranes. Several herpes viruses have been associated recently with malignancies in man and animals (KLEIN, 1972). Herpesviruses are ubiquitous and have been described in over 30 different species (HUNT and MELENDEZ, 1969; WILDY, 1971; FARLEY et aI. , 1972; KAZAMA and SCHORNSTEIN, 1972; NAHMIAS et aI. , 1972; ROlZMAN et aI. , 1973). Their widespread occurrence in nature suggests a common ancestor.