Viruses, Cancer Cells, and the Genetic Concept of Virus Infection*

S. E. LURIA

( Department of Biology, Massachusetts Institute of Technology, Cambridge, Mass. )

CELLULABGROWTHCONTROLSANDTHE ly metabolic (79). The immunological control CANCERCELL mechanisms act presumably through specific "marker groups," located mainly on cellular The experimental evidence for the role of vi ruses in the etiology of some cancers has recently surfaces and acting as receptors for antibodies been reviewed by several investigators active in (9). Alteration of immunological controls may this field (3, 25). A review by an outsider would result either from acquired tolerance by the ani only add confusion to an already complex field. mal or from loss of markers on the cells (41). This is one justification for not attempting any Local regulation among neighboring cells may be detailed survey of tumor viruses in this paper. exerted by accumulation of metabolites, by trans Another, possibly a more valid one, is that this port of macromolecular constituents, or even by conference may concern itself at least as much direct exchanges through cytoplasmic bridges; with the place of virology in cancer research as no definite evidence seems to be available. with the role of viruses in cancer. A useful intro Evidently, the key problem in cancer research duction for the presentations that will follow is to clarify the mechanisms that control cellular mine may be, therefore, a survey of recent ad growth and the cellular alterations that make the vances in basic virology, which have produced tumor cell deficient in internal controls or un some unifying concepts on the relation of viruses responsive to external ones. Several changes may to cellular constituents and to cellular functions. be needed before the full neoplastic powers of an altered cell are expressed. This is reflected in Before discussing viruses, however, it seems the so-called "progression" toward the fully ma desirable to state some problems of cancer etiol ogy in very simple terms, so that we can see what lignant state, in which a number of cellular prop is required of viruses when they are called upon erties can be altered in a series of discrete steps to act as carcinogenic agents. (22 ). Only one or a few of these steps may con A cancer cell is a cell that has become intrin cern the growth control mechanisms. sically altered and capable of multiplying by es The most productive hypothesis is that the caping the normal growth regulation by certain basic controls, which keep the normal, differen control mechanisms. The control mechanisms can tiated cell of the adult animal from dividing and be either internal or external to the cell. The in which regulate the growth and division of the stemline cells of continuously renewed tissues, ternal control mechanisms presumably include are "systems responsible for negative feedback interactions among cellular constituents, as well on specific enzyme-forming systems required for as receptor systems for external factors. The ex cell division" (66). These include, probably, sys ternal mechanisms that regulate cellular multi plication are partially known from studies on tems needed for the synthesis of DNA and of specific mitotic proteins. The full-fledged cancer compensatory hyperplasia and regeneration, on the function of endocrine glands, and on tissue cell has lost these regulatory systems, so that its transplantation ( 77 ). They include hormonal and ability to divide has become unrestricted. In ad immunological mechanisms, as well as somewhat dition, it has acquired a variety of new properties elusive mechanisms of local regulation. The sites that render it destructive to the organism as a of action of hormones on cell functions are main- whole. * Aided by grants from the National Science Foundation Among the many biochemical peculiarities of ( G-8808 ) and the National Institutes of Allergy and In cancer cells, it is difficult to decide which are fectious Diseases, National Institutes of Health (E-3038). primary and which secondary to the altered 677

growth pattern. For example, the loss of a variety known tumor viruses is a direct one on the tumor of catabolic enzymes, as well as of other proteins cells. These cells are carriers and producers of such as the organ-specific antigens (82), could the virus; they have specific properties correlated be secondary to a release of the synthesis of the with the specific virus strain ( 70, 80 ); and in vitro bulky mitotic apparatus (77). At the metabolic transformation of normal cells into tumor cells level, promising candidates for key roles in the by virus infection can be demonstrated, for ex normal repression of cell division may be path ample, with the Rous sarcoma virus (55). How ways that waste or destroy metabolites necessary ever, susceptible cells do not necessarily give a for the synthesis of DNA (61); a block in such tumoral response to a tumor virus under all cir a pathway may be sufficient to unleash unre cumstances. Thus, with polyoma virus, the tu- stricted cell growth. Alternatively, activation or moral response probably requires conditions that induction of a normally repressed protein-form obtain only in certain cells and tissues at specific ing system could produce a similar effect. Once stages of the development of the animal host or the growth-restricting mechanisms fail to func at specific stages of the viral disease. tion, it may be expected that secondary changes The role of a virus in the cells of the virus- will accumulate in the expanding populations of induced tumor is the central problem in cancer multiplying cells. virology. Clearly, the relationship of the virus to the evolution of the tumor cell may include a SOMATICCELLMUTATIONANDVmus INFECTION variety of alternatives. At one extreme, the virus Whatever the underlying biochemical mech may master-mind the whole process; at the other anisms may be, the cellular changes leading to extreme, it may trigger only a single step. Other cancer can stem from two types of events. factors may intervene, either to promote the can On the one hand, they may occur either in an cer career of some cells in a virus-infected indi vidual, as with mammary cancer in mice carrying apparently spontaneous way, or after exposure Bittner's virus ( 13), or to transform a less malig to some relatively unspecific agent (chemical carcinogens, radiation, or hormones, acting di nant into a more malignant cell, as with Shope rectly or indirectly [39] ), or following changes in papilloma (72). Thus, the virus may be respon neighborhood relations among cells, such as cul sible for one or several of the recognized steps of tivation in vitro or insertion of plastic films or carcinogenesis: initiation, promotion, and pro other inert barriers between layers of tissue ( 1). gression to full malignancy. Only rarely are the cells involved in cancerization In the evolution of virus-induced cancers, in exceptional cells to begin with, such as embry fective virus may be recoverable at one stage and onal residues. More often, the cells that embark not at another. When present, the virus is often on a neoplastic career appear to be a more or difficult to transmit to uninfected animals; the question arises, therefore, whether exogenous in less random sample from a population of normal fection, or "vertical" transmission through the cells. The randomness of the process is distinct from the orderly processes of differentiation ob germ cells or the genital tract, or even de novo served in normal development; rather, it recalls origin from noninfective proviruses or other cel the randomness of mutations affecting the genetic lular constituents, may be implicated for the material. Hence, the hypothesis that somatic cell presence of these viruses in the animals in which they are found. Especially with agents such as mutations are responsible for the initiation and Gross's mouse leukemia factor (27), the narrow progression of cellular changes toward cancer has been very popular among biologists (9 ). host-range specificity and the difficulty of trans On the other hand, essentially similar cellular mission by extracts suggest a remarkably ineffi changes toward neoplastic behavior are observed cient adaptation to natural spread. in a number of instances following infection with It has been customary to contrast the hypoth viruses (25, 70). The virus-induced tumors in esis of somatic cell mutation as the cause of can clude all varieties, from benign to the most ma cer with the hypothesis of a viral causation (9, lignant; and virus-induced tumors may exhibit 71). Nevertheless, according to current ideas progressive changes toward malignancy similar about viruses and cellular genetics, the opposi to those observed in other tumors. tion between the two hypotheses is probably Although in some instances a virus could pos more semantic than substantial. sibly act as an indirect carcinogen, by altering A somatic cell mutation may be defined opera control mechanisms normally exerted by the tionally as a cellular change which affects more virus-infected cells on other organs or tissues, in or less stably the whole clone that stems from the most instances the carcinogenic action of the changed cell. It is important to emphasize that,

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1960 American Association for Cancer Research. LuRiAâ€”GeneticConcept of Virus Infection 679 at present, in dealing with mammalian cells, we mutually exclusive. Rather, virus infection may can hardly be more specific and that we must be considered as a class of cellular mutations: a refrain from attributing to the term "somatic mu class of mutations, in fact, in which we know tation" any connotation implying a specific struc that the primary change, the entry of the viral tural or genetic mechanism. genome, is a genetic change. Undoubtedly, the The permanent cellular change might be of any primary alterations of virus-infected cells, except one of several types: gene mutations; chromosal for a few changes that may reflect trivial conse rearrangements; mutations in some nonchro- quences of viral attachment and penetration, re mosomal genetic determinants ( plasmids or para- sult from the genetic functions of the viral gen genes [33, 43] ); or alterations in self-maintaining ome. These include genetic replication, gene steady-state mechanisms regulated by metabolic function (that is, control over specific biosyn- feedback. This is the same range of mechanisms theses ), and functional interaction with host-cell that must be considered in connection with the genes. cellular changes underlying the normal tissue The genetic concept of virus infection appears differentiation (78), which involves nuclear as to be a fertile one, especially because it provides well as cytoplasmic alterations (6 ). us with a workable prototype of the cellular The most important distinction is between ge changes that can cause cancer. Knowing the ge netic and epigenetic mechanisms of cellular netic nature of the primary change, we can ana change (20, 61). A change is defined as genetic lyze the exogenous genetic component in relative (or nucleic [44] ) if it alters the genetic materials isolation and measure the amount of genetic in of the cell, that is, the structure, size, or number formation it carries; we can alter this genetic of the coded macromoleculesâ€”nucleic acidsâ€”that material in controlled ways; we can observe its carry large amounts of detailed information compatibility with other genetic elements and its usable for coding other molecular species. Epi function in different host cells. We can study the genetic (or epinucleic) changes are changes in peculiar properties that make the viral genetic the expression of genetic potentialities, such as material adapted for transfer from cell to cell activations, inhibitions, or competitive interac and, in so doing, discover transitions between tions, whether exerted at the level of primary viral and nonviral constituents of the cellular action of genetic elements or at other levels of genome. cellular metabolism. Once we consider viruses as genetic elements, The distinction between genetic and epigenetic specialized for transfer because they possess cer types of somatic mutations is relevant to the tain specific genetic functions, but otherwise akin question of viral infection, because it is now to the genetic materials of all cells in basic struc widely held that the essential constituents of ture and in primary action, we can formulate viruses are genetic elements. In fact, virus infec meaningful questions about latency, persistence, tion has been interpreted as a kind of infective hereditary transmission, and even de novo ap heredity ( 43, 51 ). Three groups of findings un pearance of viruses, as well as about the transfer- derlie this viewpoint in virology: the central and ability of genetic elements not endowed with often exclusive role of viral nucleic acid in ini specialized devices for transfer. tiating virus infection; the interactions between It seems especially important, whenever a viruses and genetic constituents of the cell; and transmissible subcellular agent is found to be the viral control of cellular functions through responsible for a pathological condition such as determination of the structure of specific pro cancer, to ask whether the agent is a virus, that teins. The concept of viruses as agents of infec is, a genetic element with a specialized infective tive heredity underlies some recent definitions of form, or a cellular constituent that can acciden viruses (51,54). According to this concept, a tally withstand the artificial manipulations in virus is considered as a genetic element, consist volved in the transmission test. ing of RNA or DNA and adapted for cell-to-cell Such questions have been raised by every stu transfer because it can determine the biosynthesis dent of viruses and cancer. Our point is that the of specific proteins for the shell that surrounds questions can be put into operationally answer the mature, infective virus particle. Some of the able form only in terms of cellular genetics, pertinent evidence will be discussed in the fol based, on the one hand, on the structural bio lowing sections. chemistry of genetic materials and, on the other It seems, therefore, unnecessary to consider hand, on the biochemistry of gene action and the somatic mutation hypothesis and the virus cellular regulation. hypothesis of cancer origin as alternative and The genetic approach to virology has been rei-

atively successful in the study of bacterial virus the female cell; the transfer can be interrupted es: bacterial genetics, phage research, and the mechanically or by DNA-breaking events (36). study of biosynthetic regulation in bacteria, de Even short fragments, once transferred, can act veloping hand in hand, have provided us with a as donors of genetic factors, which become inte satisfactory, if still incomplete, picture of the grated by genetic recombination with the chro functional organization of the bacterial cell. The mosome of the female recipient. Thus, the ge stage is now set for a similar approach to the netic results of mating and of transformation are genetics and virology of animal cells. Animal operationally similar. cells, normal or abnormal, chosen almost at will Two groups of findings need stressing. First, for genetic or pathological reasons, can be culti the DNA of each group of bacteria has a charac vated in carefully controlled chemical environ teristic base composition ( 14). Successful genetic ments (17,67). Genetic changes, such as muta recombination has been observed only between tion, chromosomal alterations, and even genetic organisms of the same base-ratio group; a simi recombination ( if it occurs ) can be detected and larity of base ratios may be required to permit analyzed. Virus infection, especially the various the DNA to participate in closely homologous steps of cellular reactions to a virus, can be pairing. ( Such "code similarity" is probably also studied with precise quantitative methods (16). required for successful integration of a phage In this "microbiological" approach to the func with the bacterial chromosome, but not for vege tional organization of the mammalian cell, the tative phage multiplication; see below.) Within bacterial picture is widely used as a model. It is, a given group of bacteria with the same base therefore, useful to discuss in some detail those composition, successful integration of factors aspects of bacterial genetics that relate to the from the donor chromosome, as measured by the controls over cell functions and to the role of in frequency of integration, depends critically on fective heredity, including viral infection, in these the degree of genetic homology between donor controls. Needless to say, the situation in bacteria and recipient; the closer the philogenetic rela should not be taken as an analogical model by tionship, the higher the frequency (53, 73). which to interpret phenomena observed in other Second, if we assume the (unproved) hypoth organisms, but as a methodological model illus esis that the nucleotide sequence in DNA acts trating the approaches and concepts that have as a code for the amino acid sequence in proteins proved useful in a more advanced field. (11) we can evaluate from data on infective heredity the "coding ratio" between DNA and After discussing the present status of bacterial viruses in the framework of the genetics of the protein. The best current estimate is 4 or 5 nu- bacterial cell, we shall discuss some recent find cleotides per amino acid ( 46 ), in fair agreement ings in animal virology that provide additional with theoretical expectations of a 3:1 minimum leads for the study of infective heredity at the ratio (11). cellular level. Another application of infective heredity in bacteria is the analysis of control mechanisms BACTERIALGENETICSANDINFECTIVEHEREDITY over gene action by the study of the function of A bacterial cell, typified by Escherichia coli, newly entered genes. The essential conclusion is contains one or more nuclear equivalents, each that the function of genes that determine specific consisting of a single chromosome-like structure enzymes is regulated by specific repressors pro with a linear genetic map and a continuous ma duced under the control of other genes (regu terial backbone consisting mainly or exclusively lating genes [64]). This mechanism is related to of DNA (36). This DNA presumably carries the the well known situation, observed in bacteria basic genetic information. In some bacterial spe and also in mammalian cells ( 12), in which exog cies ( although not yet in E. coli ) most and pos enous or endogenous metabolites control by re sibly all hereditary traits can be transferred from pression the function of specific enzyme-forming one cell to another by fragments of purified systems ( 26, 59 ). These metabolites may actually DNA, each fragment carrying one or more ge be transformed into specific represser substances netic factors in linear sequence; the transferred by the action of the regulating genes ( 10 ). Exog factors become integrated in the genome of the enous inducers presumably act by relieving the recipient cell. This transformation (32) is the repressions that normally prevent the function of most striking example of infective heredity. inducible genes (64). When a male (Hfr) and a female (F~) cell The systems of repressive functions in bacteria of E. coli mate, there is an oriented, generally provide the most promising model for the anal incomplete, transfer of a male chromosome to ysis of the controls that maintain alternative

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1960 American Association for Cancer Research. LuRiAâ€”GeneticConcept of Virus Infection 681 functional states of a cell (63). Similar controls ond, the nature of the regulatory interplay be presumably function in the regulation of growth tween mutually exclusive functions. versus nongrowth states. Any genetic change, Genetic nature of phage functions.â€”The ge- whether endogenous or viral, that would produce iletic nature of the primary action of phage is inability to repress a reaction needed for cell elucidated by the effect of phage mutations. division might unleash uncontrolled growth ( 66 ). Thus, for example, the series of reactions leading The bacteria do not provide clear models for to lysogeny require at least three steps controlled the mutual antagonism between reproduction by three adjacent phage loci; mutations within and differentiation, which is observed in many these loci prevent or hinder lysogeny and in animal tissues. There is, however, in bacteria one crease the virulence of the phage ( 38, 45 ). The instance of reversible differentiation, namely, initiation of vegetative phage multiplication, on spore formation, in which growth is arrested the other hand, requires certain key functions when new functions and structures appear in the that are controlled by specific phage genes, since bacterial cell. Recent genetic analysis by means they can be suppressed by prophage mutations of transformation indicates that spore formation which render the prophage defective (34). The results from a release of controls over the syn defective prophage can continue to multiply in thesis of certain specific proteins and is physio association with the host chromosome and to logically comparable to an induced biosynthetic control a number of cell properties; but it can process (74). neither initiate vegetative multiplication nor pro duce mature virus particles (unless the blocked PHAGEINFECTIONASINFECTIVEHEREDITY genetic reactions are supplied by an unmutated The phenomena observed in phage infection phage of the same species). The mutation that fit and complete the above picture of the func makes a prophage defective transforms a viral tional genetic organization of the bacterial cell. element into what we may consider as a nonviral The phage particle consists of a core of DNA in one, since it has become unable to control the a protein shell equipped with devices for inject production of mature virus particles. ing the DNA into the bacterium (28 ). The entry The structure of phage-coat proteins can be of phage DNA into a susceptible bacterium ini altered by phage mutations and is under the tiates a variety of reactions, which may be com coding control of specific phage genes (5, 76). patible or incompatible with one another and Interestingly enough, with the temperate phages with other cellular functions. One series of reac it is the initiation of the synthesis of coat proteins tions leads to lysogeny, with spatial and repro that coincides with irreversible events incompat ductive integration of the phage genome, as pro- ible with persistent bacterial integrity. The con phage, with the bacterial chromosome. Another tinued life of the cell appears to depend on sup series of reactions that can be initiated, either by press ive control over a set of specific syntheses. entry of a phage or by "induction" of a prophage, Another set of new functions in phage-infected leads to the vegetative multiplication of the cells is the appearance of unusual enzyme ac phage genome, the production of phage-coat tivities, by which intemperate phages prevent proteins, the maturation of phage particles, and the synthesis of normal bacterial constituents and the formation of lytic enzymes that permit the retool the synthetic machinery in order to make new phage particles to be set free. phage. The most remarkable ones are the en In addition, phage infection may produce a zymes that shift the synthesis of DNA from host variety of alterations in bacterial functions. Some type to phage type in bacteria infected with the of these alterations, such as changes in the anti T-even phages. The DNA of these phages, in gens of the bacterial surface (81), are mutations stead of cytosine, contains 5-hydroxymethyl cyto- perfectly compatible with cell life; others, such sine, which may be variously glucosylated (83). as the release of destructive enzymes, lead inev Within a few minutes after infection of a bac itably to the death of the bacterium. We call terium with one of these phages, a whole set of temperate a phage that can achieve the prophage new enzyme activities appears. Some provide state and establish lysogeny; virulent a phage building blocks for the new DNA; others carry that is genetically incapable to do so; and intem out its glucosylation; still others destroy specific perate a phage that initiates destructive processes as a prerequisite to its own replication.1 1 These terms can be defined for phage in more specific manner than the terms moderate, submoderate, and cyto- Two sets of considerations are most relevant cidal, which have been proposed to describe various types here: first, the nature of the primary action of of relations between animal viruses and their host cells phage in controlling cellular functions; and, sec (15).

intermediates for host-type DNA or degrade the ing animal viruses and their host cells in this prÃ©existentcellular DNA to fragments usable for respect. phage synthesis ( 21, 40, 42, 65 ). In this instance, It is interesting to speculate also on the possi the virus appears to take over completely the bility that the mechanisms that regulate or sup control of the biosynthetic function of the cell; press cell division in differentiated animal cells but even this radical shift can be traced to rel may include inhibitions on DNA synthesis acting atively few changes in key reactions. The most specifically on DNA of a characteristic base com interesting reaction, as a possible model of regu position. Entry of DNA elements of different lation of cellular growth, is one that specifically composition, such as DNA viruses, might con degrades deoxycytidinetriphosphate to the mono- ceivably upset the repression system and unleash phosphate, thereby preventing the synthesis of uncontrolled cellular growth and multiplication. host type DNA (40,42). In a normal cell, such Regulation of alternative sets of phage-con- an enzyme could prevent DNA synthesis and, trolled functions.â€”The role of specific repression therefore, suppress cell division. In turn, a block mechanisms in the regulation of phage functions in the synthesis of such an enzyme could unleash is best illustrated by the phenomenon of immu cell proliferation and lead to unrestricted cellular nity, clarified largely by the work of Jacob and growth. his colleagues (34). Once a temperate phage be There is as yet no proof that the new enzymes comes prophage, vegetative multiplication of the appearing after infection with T-even phages phage genome ceases, its maturation is pre are directly coded by phage genes. It is interest vented, and the multiplication of similar phages ing, however, to estimate the amount of genetic introduced by superinfection in the lysogenic information contained in a phage. The DNA of cells is also inhibited. The lysogenic bacteria are a phage like T2 contains about 2 X IO5 nucleo- immune to superinfection with phage similar to tide pairs, enough, according to current views the prophage. The mechanism of this immunity (11), to code 7 X 10* amino acids, that is, about is the production of specific represser substances 70 protein molecules of average molecular weight which, acting through the cytoplasm, prevent the 100,000. (The DNA in an E. coli nucleus con vegetative multiplication of the phage and the tains about IO7 nucleotide pairs.) Even if only synthesis of the phage-coat proteins. Destruction one-third of the T2 DNA is genetically relevant of the repressor substance is probably the initial (47), it can still code over twenty such proteins; step in the induction of vegetative phage multi this can account for many biochemical functions. plication from the prophage state. By mutation, Other phages, however, are smaller; the small a phage can acquire the ability to produce the est ones, such as those of the S13 group, have a immunity substance even when not yet estab single strand of DNA with about 5000 nucleo- lished as prophage (35). The analogy with the tides (75), which could code 1600 amino acids. repressive regulation of enzyme biosynthesis is The coat of these small phages consists of twelve quite close (34). protein units, each containing about 4000 amino We may ask if specific repressers of the im acids. Assuming, by analogy with the small munity type play some role in maintaining the plant and animal viruses, that all protein units genetic constancy of the bacterial cell by pre are identical and that they are not built up from venting the anarchistic replication of chromo smaller identical subunits, there would hardly be somal bits. There are in bacteria, besides the enough genetic information available in this phages, other dispensable genetic elements or phage to determine the protein coat, let alone episomes (37), which can be either present or other proteins. Most effects of the phage on the absent from a cell and which can either multiply cell would have to be indirect, secondary to the vegetatively or attach themselves to certain chro extremely few genetic actions that initiate phage mosomal sites. When attached, they multiply synthesis. with the chromosome and suppress further vege With the intemperate phages, even in the ab tative multiplication. Some episomes, such as the sence of specific host-destructive biosyntheses, fertility factors of E. coli, can be transferred by the switch between host-controlled and phage- contact from cell to cell. The genetic functions controlled patterns of synthesis might be due to controlled by episomes are clearly unessential different DNA base ratios; competition between for cellular life since an episome can be lost with two incompatible templates for the DNA-synthe- out death or damage to the bacterial cell. sizing enzymes might cause a complete shift from Attachment of a genetic element, such as an using one set of directions to using the other. episome or a temperate phage ( itself an episome It will be worth while comparing DNA-contain- with potential viral functions ), to a chromosomal

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1960 American Association for Cancer Research. LuRiAâ€”Genetic Concept of Virus Infection 683 site can probably activate specific genetic func sufficient phage development; but this may well tions not only in the episome itself but also at be accidental. A piece of bacterial chromosome neighboring chromosomal sites. An episome such might, however, become part of a phage element whose viral functions remain fully effective. This as the fertility factor, which can attach itself at could be the mode of origin of "converting" any one of many chromosomal sites (37), may produce a variety of different genetic results. phages, which contain in their genome some This situation is not without counterpart in genes that control cellular properties, such as sur higher organisms. Genetic elements that can as face antigens, which have no apparent relation sume different chromosomal locations and acti to the viral functions of the phage (81). vate neighboring genes are known to occur in maize (7, 57). One wonders as to the possible PHAGEANDOTHERVIRUSES role of changes in state and position of such The findings outlined above illustrate the basis genetic elements in determining the response of for the integration of phage research and bac cells to external stimuli such as carcinogenic terial genetics into a unified subject. Will such agents. an integration be possible and valid for other The episomes provide examples of the two virus-cell systems? ways by which an added, unessential genetic ele On the one hand, the intimate relationship of ment can persist in a clone of cells: (a) persist phages to the bacterial chromosome need not ence in a form materially and reproductively in disqualify them as model viruses. Phages are tegrated with the chromosomal apparatus of the simply a group of viruses whose relation to host- cell; (Â£>)persistence by autonomous vegetative cell organization is already fairly well under multiplication. These are the two kinds of state stood. On the other hand, the bacterial model which the genome of a persistent virus may has important limitations. For example, RNA assume in its host cell. It is interesting to point transfers have not yet been observed in bacteria, out that at least one episome, the fertility factor and the phage model may prove misleading if in E, coli, can be eliminated by chemical treat followed too literally in the exploration of RNA ments of the bacteria that carry it in the non- viruses. Also, the bacterial model does not pro integrated condition (29). This may provide an vide any direct analogy for those regulatory interesting lead to the chemotherapy of some processes that depend on interactions among dif persistent virus infections. ferentiated cells in a complex organism, nor for It is also worth recalling that for temperate the role of viruses in altering these regulatory phages, as well as for other bacterial episomes, processes. the chromosomal location and the number of The phage model has a close counterpart in at copies of the integrated form can be determined least one instance of genetic control of host prop only by tests of genetic linkage and of genetic erties by a group of animal viruses, the agents competition between related elements ( 4 ). Simi that produce sensitivity to CO2 in Drosophila lar tests will be needed to analyze the genetic (48). The responsible agent, virus a, can assume condition of persistent viruses in animal cells. in the flies two alternative conditions resembling Transfer of bacterial genes to phage.â€”Tem the vegetative and prophage states. The "pro- perate phages illustrate not only how viral genes viral," stabilized form exerts a repressive influ become integrated with the bacterial chromo ence on vegetative multiplication, recalling that some, but also how chromosomal genes can be of prophage. Stabilized a can mutate to defec- come part of a phage element. This is observed tiveness, that is, to inability to produce the ma in special transduction (2, 52, 60 ). In the known ture infective forms. The reverse mutation is cases, the gal (galactose utilization) genes can also observed. The stabilized form of virus

ular transmission of a virus through gameto- cific biochemical activity appears in the cells of genesis and fertilization. Such transmission is not a virus-induced tumor, it becomes important to exceptional in insects; many plant-pathogenic decide whether this activity is directly controlled viruses are regularly transmitted in their insect by viral genes, because any such new function vectors from one generation to the next through has a significant chance of being the key function the egg (56). The case of a is the only one in in the tumoral transformation. The most intrigu which the genetic analysis has implicated a ge ing case ( 69 ) is that of arginase, which is found netically stabilized proviral state. at high levels in the cells of viral papillomas of Incidentally, it seems worth mentioning here rabbits as well as in the cancers that originate the possibility that insect vectors may play some from the papillomas ( and which presumably still role in the natural spread and perpetuation of carry the viral genome, possibly in a defective some tumor viruses that are notoriously difficult form). The tumor-carrying animals contain in to transfer mechanically by means of cell ex their blood serums a precipitin, absent in the tracts. control animals, which reacts with the tumor arginase. This finding is suggestive of a viral CONTROLMECHANISMSINVIRALINFECTIONS control over the protein specificity of the en OF ANIMALCELLS zyme (69a). Genetic analysis of this situation, We turn now to some aspects of animal virol however difficult it may appear at the present ogy that concern the role of viruses in the genetic time, should be very rewarding. control of cellular properties. Cellular controls over viral maturation.â€”With Viral control over cellular functions.â€”First, let bacteriophage, as well as with some animal vi us consider once more the coding ratio. Animal ruses, there have been observed "host-induced viruses include both DNA and RNA viruses modifications" (31, 50), in which the host-range (whereas all the plant viruses that have been of a virus is altered in a reversible way. The al analyzed contain RNA). Since viral RNA can teration may be a restriction of the range of host initiate infection and can control the production cells in which the virus can multiply. The mech of complete virus (30), including the exact rep anism of these modifications is unknown, but it lication of mutational changes, the RNA must act probably operates on viral maturation. The pos genetically. It seems reasonable to assume that sible role of host-induced modifications in tumor- the coding ratio for RNA is similar to that postu producing viruses can only be guessed at. lated for (single-stranded) DNA. We find that More interesting, from the viewpoint of mech the amount of genetic information in certain ani anisms that control viral maturation, are examples mal viruses must be quite limited. Thus, rabbit of incomplete virus growth cycles. papilloma virus, with about 4 X IO6 MW DNA,2 There are at least two ways in which the mat or polio virus, with 2 X 10Â°MW RNA, can each uration of a virus into infective virus particles code about 2200 amino acids at most. Since some can fail: failure to synthesize an essential com of this code is needed for the characteristic viral ponent of the viral shell, and failure of the var proteins, not much information is available to ious components to assemble together. Incom code other proteins and enzymes. Thus, the virus- plete growth cycles in myxoviruses (the influenza infected cell is genetically not very different from virus group) illustrate both possibilities. the uninfected cell; and any switch in growth In the normal growth cycle of these viruses, pattern due to a virus must depend on one or the S element, containing RNA and protein, is few virus-controlled reactions. Most of the bio produced first and probably only in the nucleus, chemical changes in virus-infected cells, especial the hemagglutinin component is formed in the ly in virus-induced tumor cells, are probably cytoplasm, and the outer virus coat, partly con caused indirectly by an altered balance among tributed by the host cell, is assembled at the biosynthetic pathways or by secondary genetic cellular surface (8). In the chorionic cells of the alterations. It is not surprising, therefore, that the chorioallantoic membrane of the chick embryo, same key changes may result from exogenous however, the growth cycle is incomplete; only S viral infection, or from endogenous genetic nucleoprotein is formed, but no hemagglutinin changes, or from epigenetic changes due to en (24). The host-cell has become, through differ vironmental stimuli. entiation, incapable of fulfilling some of the virus- In view of the limited amount of genetic in dictated orders, and no complete virus can be formation available in a virus, whenever a spe- made. 2 This value may be too low by a factor 2 (J. D. Watson, A different situation is observed with fowl personal communication). plague virus in the L cell line of mouse fibro-

Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1960 American Association for Cancer Research. LuHiAâ€”Genetic Concept of Virus Infection 685 blasts in tissue culture (23). Infection here is though its absolute infectivity (infectious units abortive, and no new virus is produced, although per unit of nucleic acid) may be much lower all the known constituents of the virus are pro (30). This suggests that the process of matura duced in the cell. Maturation fails because the tion, on the one hand, enhances the transferabil- S nucleoprotein, although formed in normal ity of a virus by increasing its infectivity but, on amounts in the nucleus, is not released into the the other hand, restricts the range of host cells cytoplasm and cannot, therefore, participate in that the virus can parasitize. Like all adaptations, the assembly of mature infectious particles, even the adaptation of the viral genome for transfer though the other viral components, including the also limits its potential spread. hemagglutinin, have also been synthesized. This observation raises several interesting pos These situations illustrate the fact that viral sibilities. First, we may suspect that in an in maturation, and the production of complete in fected animal the occasional transfer of naked fective virus particles, may fail not only because viral nucleic acid may bring virus to certain cells of genetic changes in the virus ( defectiveness ), which may respond anomalously to it or which but also because of genetic or developmental would be virus-resistant if exposed to mature vi changes in the virus-carrying cells. rus particles. Infection of such cells, even if it In this respect, a remarkable situation is one led to production of mature virus particles, could observed in rabbit papilloma, which reveals a not spread by cell-to-cell transfer of the particles. subtle interplay between viral controls over cel Different cells would be needed as indicators in lular growth and cellular controls over viral mat testing for virus production. uration. The virus-induced papillomas consist Second, the extended host range of viral RNA of a core of proliferating epidermal cells derived suggests that the restrictions on RNA replication from the cells of the basal layer of the epidermis. may not be very stringent. This, in turn, raises Like normal epidermal cells, the papilloma cells the question whether some classes of cellular ultimately undergo keratinization and stop pro RNA, even though they have not evolved a viral liferating. The papillomas contain large amounts maturation process, may not be able to establish of virus particles, which consist of DNA in a pro themselves in a variety of cells if they can gain tein shell. Microscopic examination with fluores access to them. cent antibodies reveals that the viral protein and, A possible role of cellular nucleic acid trans hence, the mature virus are found only in the fers in the control of normal differentiation has cell nuclei (58). The significant finding is that been postulated repeatedly but has never been the viral protein is present only in the nuclei of substantiated. We may recall, however, the sug those cells that have started keratinization and gestive similarity in RNA content between the have lost their ability to divide. The proliferating small RNA viruses and the ribosomes, which con cells of the tumor do not contain any detectable tain about 2 X 10" MW RNA (68). The struc viral proteins. These cells must contain the viral tural proteins of ribosomes may bear to their genome in some naked, replicating, but presum RNA a relation somewhat analogous to that of ably noninfectious form. the protein coat of virus particles to the viral nu It appears, therefore, that the virus induces in cleic acid. Ribosomes might exceptionally be the basal type cells an increase in cellular pro transferred from cell to cell in functional form. liferation; proliferation, in turn, represses the In fact, we may even speculate whether some of synthesis of viral protein. Keratinization, a typi the more highly specialized â€¢tumor-inducing cal cellular differentiation, occurs when cell pro agents, like Gross's virus, may not be transmissi liferation stops, and at this point the synthesis of ble ribosomes. viral protein is also released. Thus, cell prolifera A recent report (18) suggests a remarkable tion is mutually exclusive with two expressions role of a virus in facilitating the transfer of other of differentiation: formation of keratin in the cell determinants of cellular functions. In these ex cytoplasm and formation of viral protein in the periments, chick heart muscle was mixed with cell nucleus. Rous sarcoma tissue, and the mixture was ex Nucleic acid transfers.â€”Fromsome of the RNA tracted to isolate the sarcoma virus. The joint ex viruses, or from tissues infected with these vi tract (but not a combination of two separate ex ruses, one can extract RNA fractions more or less tracts ), when placed on the chorioallantoic mem free of proteins and capable of infecting host brane of the chick embryo, gave rise to tumors cells and of initiating virus production. Interest that contained striated muscle fibrils in many of ingly enough, the free RNA has a wider range of their cells. This observation, if confirmed, would host cells than the intact virus particles, even suggest that a rather firm association was estab-

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S. E. Luria

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