Viral Leukemia and Lymphoma Branch National Cancer
Institute National Institutes of Health Bethesda, Maryland 20014
Extensive evidence has demonstrated that type C RNA viruses are
active agents in the causation of naturally occuring cancers. Type
C RNA viruses are a distinct class of vertebrate viruses which share
a common morphology, protein composition, and viral life cycle.
They are spherical particles containing a large single-stranded
RNA as their viral genome complexed with a RNA-directed DNA polymerase
(reverse transcriptase) in a central, symmetric, electron dense
core surrounded by a unit membrane. During viral replication the
nucleoid condenses beneath the surface of the cytoplasmic cell membrane
with subsequent "budding" of the virus from the cell surface. Type
C RNA viruses have been isolated from many vertebrate species. They
have been shown to cause a variety of naturally occurring vertebrate
neoplastic diseases, including leukemias and sarcomas of chickens,
lymphomas and related hematopoietic neoplasms and sarcomas of mice,
lymphosarcomas and fibrosarcomas of domestic cats, and leukemias
and sarcomas of some primates. Type C viruses have also been isolated
from other mammalian species such as rats, guinea pigs, hamsters,
cattle, domestic pigs, woolly monkeys, gibbon apes, and baboons
(Table 1). Recently there have been reports of isolates from human
tissues (see below). As yet, in some of these species, the relationship
between these viruses and neoplastic diseases of their host species
has not been clarified. There have also been reports of electron
microscopic observations of typical type C viral particles in tissues
from some other mammalian species, including dogs, horses, rhesus
monkeys, and in certain human tissues, but such viruses have not
yet been isolated in vitro and biochemically characterized. Type
C RNA viruses exhibit varying biological activity. Some have no
known pathological effect and others are extremely efficient in
producing neoplasias. Also, transformation may occur either with
complete or incomplete virus expression. Type C viruses have also
been detected in normal tissues; embryonic and placental tissues
show more type C viral expression than other differentiated tissues.
The viruses produced by both normal and tumorigenic tissues are
very similar to one another in their morphology, biochemical and
immunological properties (1, 2).
Table I: Mammalian type C RNA virus
Transmission of virogenes
The spontaneous appearance of complete, infectious type C RNA viruses
in animals of certain mammalian species and in cultured cells derived
from these animals led to the hypothesis that the information for
the production of such viruses might be transmitted genetically
from parent to progeny along with other cellular genes (virogene-oncogene
hypothesis) (3, 4). Activation of this normally repressed, genetically
transmitted, type C endogenous virogene information, rather than
infection from outside the animal was proposed as the most common
mechanism by which type C RNA tumor viruses produce naturally occurring
Table II: Species where a COMPLETE virogene
is known to be present in normal cells
Vertical transmission from generation to generation rather than
infection from animal to animal was postulated to be the primary
means by which the viral genes have been maintained in animal populations.
Much subsequent experimental work supports this, the most important
being that "virus-free" cell cultures (Table 2) derived from chicken,
mouse, hamster, rat, pig, cat, and baboon tissues (reviewed in 5)
can begin to secrete either spontaneously or after treatment with
chemical inducing agents, typical complete type C viruses (6, 7).
Cocultivation of the virus producing cell cultures with appropriate
permissive cell lines from heterologous species has been needed
to detect and increase virus production in several of these systems
(8-10). The properties characterizing such endogenous mammalian
type C RNA viruses which are products of the genetically transmitted
virogenes are summarized in Table 3.
Table III: Properties of endogenous type C virogenes
1. DNA of all somatic and germ cells of all the animals
in a species contain viral gene sequences.
2. Multiple related but not identical copies present
in the cellular DNA, more than DNA from a heterologous cell that
is actively producing virus.
3. Virus expression (RNA, gs antigen, polymerase,
complete particles) under cellular control. Expressed in certain
tissues at certain times during development.
4. Clonal lines either spontaneously or after induction
are capable of releasing complete virion.
5. Cells generally resistant to exogenous infection
by the homologous endogenous virus.
The endogenous type C virogenes are those sets of gene sequences
that are an integral part of the host species' chromosomal DNA and
code for the production of type C viruses. These gene sequences
contained in normal cellular DNA should be distinguished from type
C viral DNA sequences which can be added to the animal's genome
from the outside by "exogenous" viral infection and subsequent integration
(provirus formation) (11 ). Endogenous type C virogenes should also
be distinguished (Table 4) from those gene sequences not originally
present in the genome, that are postulated to arise by gene duplication
and/or recombination mediated by the reverse transcriptase mechanism
(12, 13) (protovirus formation (14)). The endogenous virogenes and
the oncogenes (those cellular genes responsible for transforming
a normal cell into a tumor cell which mayor may not be present
Table IV: Major differences between virogene and protovirus
1. Viral copies present in germ cells and somatic cells.
2. Genes maintained in population by normal cellular replication.
Reverse transcriptase not required.
3. Transformation results from activation of normally latent cellular
genes associated with and/or part of the viral gene sequences.
1. Germ cells lack virus information. Generated in rare somatic
cells by chance.
2. Reverse transcriptase plays essen tial role in generating new
3. Transformation results from the generation of new gene sequences
that do not preexist in normal cellular DNA.
as a part of the genome of type C viruses ( 4) ) are normall y
repressed, bu t can be activated by a variety of intrinsic (genetic,
hormonal) as well as extrinsic (radiation, chemical carcinogens,
other infecting viruses) factors (Table 5). Regulatory genes and
environmental factors determine the extent of virogene transcriptlon.
Table V: Implications of the virogene-oncogene hypothesis
1. All somatic cells of a species have DNA homologous to type
C virus RNA of that species (virogenes).
2. Type C viruses derived from closely related species should have
closely related specific antigens, e. g., gs antigens, polymerase
and their nucleic acid sequences should be more related to one another
than are those viruses released by distantly related species (virogene
3. The transformation specific sequences of RNA tumor viruses
should be present in normal cellular DNA (oncogenes).
4. Spontaneous, chemically induced and viral induced transformed
cells and tumor cells should have RNA as well as DNA sequences homologous
to the transform ing specific sequences found in tumor viruses (
oncogene expression) .
Type C virogene sequences offer several distinct advantages for
the study of evolutionary relationships. As cellular genes, type
C virogenes are subject to the pressures of mutation and selection;
thus, closely related animal species would be expected to have closely
related, but not identical, endogenous type C virogenes. Type C
virogenes are unique from all other known cellular genes in their
ability to give rise to the production of infectious type C virus
particles. The complete expression of virogenes, at least in some
species, with concomitant production of type C viruses containing
specific viral proteins, a reverse transcriptase, and a high molecular
weight RNA, offers a unique possibility for the isolation of a discrete
set of cellular genes and their products. Single-stranded 3H-DNA
transcripts that represent the viral RNA sequences, synthesized
in vitro by the viral reverse transcriptase, can be used to detect
information in the cellular DNA of related species. Mammalian type
C viruses are present in cellular DNA in multiple complete copies
(five to fifteen per haploid genome) as a family of related, but
not identical, gene sequences (15). These sets of type C virogenes
appear to evolve more rapidly than the unique sequence cellular
genes, possibly because of their presence in multiple copies in
each genome (16). This apparent faster rate of evolutionary divergence
of the primate type C viral genes allows a fine degree of discrimination
among the various primate species. It is thus possible to establish
taxonomic relationships among closely related species that are not
revealed by methods involving the annealing of entire unique sequence
DNA. The use of such viral probes clearly indicates that virogene
evolution has followed the pattern of overall species evolution
(16). In contrast, infectious, horizontally transmitted primate
viruses spread from animal to animal and are completely unrelated
by molecular and antigenic criteria to endogenous, genetically transmitted
primate viruses. The properties of infectious viruses traveling
from animal to animal can become rapidly altered, thereby obscuring
their origin. Genetically transmitted viruses have remained stable
enough to make it possible to detect events which occurred millions
of years ago, and precisely determine the species from which they
originated. The inability to detect viral-related sequences in more
distantly related species reflects extensive changes in base sequences
that have accumulated in the virogene since divergence (17).
Endogenous primate type C viruses
It has only been within the last year or two that endogenous type
C viruses have been successfully propagated from primates, man's
closest relatives. Several isolates from different tissues and from
different species of baboons have been obtained in this laboratory.
They are morphologically and biochemically typical of mammalian
type C viruses, are closely related by host range, viral neutralization
and interference and by immunologic and nucleic acid hybridization
criteria, but are distinctly different from all other previously
studied type C viruses (10, 18). ³H-DNA transcripts prepared from
three of the baboon type C virus isolates hybridize completely to
DNA extracted from various tissues of several different healthy
baboons (18). These type C virus isolates satisfy all the criteria
for endogenous, genetically transmitted viruses of primates. The
finding of DNA sequences in normal tissues is one of the strongest
pieces of evidence that the viral information is , maintained in
the population as cellular genes. J If the baboon type C viruses
were truly endogenous primate viruses (10) and had )1 evolved as
the species evolved, then it appeared reasonable to suspect that
other Old World monkeys that are close relatives to the baboon would
have related vic rogene sequences in their DNA. Primate species
more distantly related taxonomi, cally to baboons would be expected
to have more extensive mismatching of their virogene DNA sequences
as measured by the thermal stability of nucleic acid hybrids formed
or by the final extent of hybridization (19, 17). The study of the
evolutionary relationships of type C viral gene sequences is especially
favorable in primates since much is known about the evolutionary
rela tionships between primates: the fossil record has been intensively
studied as Homo sapiens have been particularly interested in their
own origins. The Old World monkeys (which include the baboon species)
have been separated from the great apes and man for 30 to 40 million
years. The New World monkey branch diverged from the common stem
leading to both the apes and the Old World monkeys, approximately
50 million years ago while the prosimians evolved from primitive
mammalian stock roughly 60 to 80 million years ago. Hybridization
studies employing a DNA copy of the baboon virus RNA were used to
detect type C viral nucleic acid sequences in primate cellular DNA.
Multiple copies of viral gene sequences related to the RNA genomes
of the baboon type C viruses are found in all other Old World monkey
species, higher apes, and are also found in man. However, no homology
can be detected in various New World monkey DNAs (17). The degree
of relatedness of the virogene sequences closely correlates with
the txonomic relatedness of the monkey species based upon anatomic
criteria and the fossil record. The results establish that, within
the primates, type C viral genes have evolved as the species have
evolved, with virogenes from more closely related genera and families
showing more sequence homology than those from distantly related
taxons. That such species as the baboon and rhesus monkey, which
have diverged genetically and have been geographically separated
for several million years, still retain related virogene sequences,
and the low, but consistently observed, hybridization to ape (chimpanzee)
DNA with the baboon viral probe, demonstrates that this virogene
information has been conserved in the primate stock during the course
of evolution as stable cellular elements for at least 30 to 40 million
years (17). The ubiquitous presence of endogenous type C virogenes
among anthropoid primates and their evolutionary preservation suggest
that such genes provide functions with a selective advantage to
the species possessing them. Virogene information is not only present
in other Old World primates, but is also normally expressed. Probes
from the baboon virus isolates have detected viralspecific RNA in
rhesus monkey, stumptail and green monkey liver tissue; and p30
antigen has been found in normal stump tail spleen tissue and in
a rhesus ovarian carcinoma (20). Two human tumors, an ovarian carcinoma
and a lymphocytic lymphoma, have also been found to contain primate
type C viral p30 antigen (21). These genes, therefore, are not inactive,
but are normally expressed; the leve], however, varies from animal
to animal and from tissue to tissue in a given animal.
Interspecies transfer of type C virogenes
Type C viruses have also, under natural conditions, been transferred
between species that are only remotely related phylogenetically.
In some instances, type C virogenes have escaped host control as
virus particles infectious to other species. These viruses can be
transmitted from one species to another with integration of their
information into the DNA and subsequent perpetuation through the
germ line of the recipient species. Because of the stability of
the viral gene sequences when they are incorporated into cellular
DNA, events that have occurred millions of years ago still can be
recognized by examining the genetic information of the virus and
that of the host cell. One can assess the relatedness of a given
virus to the host it is associated with by comparing (using molecular
hybridization) the match between the viral RNA genome and the DNA
of cells from an animal of the species with which the virus is associated.
Endogenous viruses from one species horizontally transmitted to
another species are related to, but distinct from, one another by
many different criteria: nucleic acid sequence homology, antibody
inhibition of polymerase activity, antigenicity of the p30 protein,
viral interference and viral neutralization. Three known examples
of trans-species infections by endogenous type C genes are discussed
below. One example involves the transfer of an endogenous primate
type C virus into the germ line of the ancestor of the domestic
cat (22, 23 ). Results have shown that domestic cat DNA contains
sequences partially related to endogenous baboon type C viral sequences,
even though unique sequence baboon and cat cellular DNA show no
homology. Since other mammals do not contain those related sequences,
the finding of baboon type C viral sequences in the distantly related
domestic cat (Felis catus) cannot be explained strictly on evolutionary
grounds (17). Domestic cat DNA contains type C virogenes which can
lead to the production of endogenous RD-114/CCC viruses (24, 25).
In comparing the endogenous primate viruses to this feline group
of viruses we found that they are related to each other, but can
be distinguished by biologic and immunologic criteria and by partial
nucleic acid sequence homology. Endogenous viruses from one group
of mammals (primates) are concluded to have infected and become
apart of the germ line of an evolutionary distant group of animals,
progenitors of the domestic cat (22, 23 ) and thus have had a common
ancestor even though they now behave as endogenous viruses of two
taxonomically distant mammalian species. Genes related to the nucleic
acid of an endogenous domestic cat type C virus (RD-114/CCC) are
found in the cellular DNA of anthropoid primates while at the same
time many members of the cat family Felidae lack these sequences
(Table 6 ).
Table VI: Relationship between cat and baboon endogenous
type C virus
1. The cat (RD-114/CCC) and baboon virus groups are related but
distinct from one another by:
a. Viral DNA-RNA hybridization,
b. Inhibition of polymerase activity by antibody,
c. Antigenicity of the p30 protein,
d. Viral interference, e. Viral neutralization.
2. Cat and baboon unique sequence DNA markedly different, species
diverged from one another over 80 million years ago.
3. Cat (RD-114/CCC) virus DNA transcripts hybridize to the DNAs
of all Old World Monkeys and apes, and to the DNAs of domestic cats
and certain other Felis species.
4. Baboon (M7/M28) virus DNA transcripts hybridize to the DNAs of
all Old World Monkeys, higher apes, and man, and to DNAs of those
Felis species which contain RD-114 related sequences.
From the relatives of the domestic cat that have RD-114/CCC viral
genes and from those that did not acquire them, we have concluded
that the infection occurred 3 to 10 million years ago, in Africa
or in the Mediterranean Basin region before the Old World monkeys
had significantly diverged. This absence of RD-114/CCC related information
in other cats is consistent with acquisition of this virus relatively
recently in feline evolution. Experiments have shown that, besides
the RD-114/CCC cat viruses which were transmitted from primates
to cats (as described above), another distinct class of type C RNA
virus was acquired by cats and is now present in their germ line.
These feline leukemia viruses (FeL V) were transmitted from an ancestor
of the rat to ancestors of the domestic cat and their close relatives
(26 ). The relationships observed between FeL V and the endogenous
viruses of rodents are similar to those between endogenous feline
viruses of the RD-114/CCC group and endogenous primate type C viruses.
FeL V -related gene sequences are found not only in the cellular
DNA of domestic cats but also in the DNA of three other closely
related Felidae (Felis sylvestris, F. margarita, F. chaus). More
distantly related Felis species lack FeL V -related virogenes, while
the cellular DNA of rodents, in particular rats, contains related
virogene sequences. This suggests that FeL V -related genes were
introduced into the Felis lineage foIlowing trans-species infection(s)
by type C viruses of rodent origin. The absence of FeL V -related
DNA sequences in most of the Felidae indicates that these genes
were acquired subsequent to the initial Felidae divergence in evolutionary
history but prior to the radiation of the above four Felis species.
It is interesting that cats which contain sequences related to RD-114/
CCC genes also contain FeL V -related genes, while other members
of the Felis species lack both sets of sequences. Both groups of
viral genes appear to have been introduced to the cat germ cells
from distinctly different groups of animals (rodents and primates)
(26). The third example of trans-species infection is that of an
endogenous virus acquired by an ancestor of the domestic pig from
an ancestor of the mouse (27). Pig ceIl cultures produce type C
viruses (28-31) that are genetically transmitted and present in
all pig tissues in multiple copies in the cellular DNA (31, 15).
Partially homologous viral gene sequences are also found in rodent,
in particular Muridae, ceIlular DNA (27). Close relatives, such
as the European wild boar and the African bush pig, have closely
related viral genes in their DNA. The nucleic acid homology between
the endogenous pig type C viral RNA and murine cellular DNA suggests
that the endogenous viruses had a common ancestor. It can be shown
that this virus was acquired by an ancestor of the pig from a small
rodent related to the mouse (27). From the extent of hybridization
of the pig type C viral DNA probes to rodent cellular DNA, the type
C virogenes were introduced into the Suidae lineage by trans-species
infection from members of the family Muridae after the mouse had
separated from the rat, but before the different species of mice
had diverged from each other. Rodent viral genes thus gave rise
to infectious particles that became incorporated into the porcine
germ line. The rate of evolution of the virogene sequences in the
pig appears to be much slower than that of genes that have remained
in the rodent lineage; this may be a consequence of transfer from
a shorterlived animal (the rodent) to a longer-Iived one (the pig)
(27). The time of gene transmission is estimated as occurring 5
to 10 million years ago and it is concluded
Table VII: Examples of transmission of
type C virus genes between species
that the present-day porcine type C virogenes most closely approximate
the viral genes as they were 4 to 6 million years ago in the rodent
lineage (27). The data as summarized in Table 7 demonstrate that
viral genes from one group of animals can give rise to infectious
particles that not only can integrate into the DN A of animals of
another species, but can also be incorporated into the germ line
(germ line inheritance of acquired virus genes). Clearly, if viral
gene sequences can be acquired in this way, it is possible that
type C viruses have served to introduce other genes from one species
to another, and may provide an important mechanism by which species
stably acquire new genetic information.
The infectious primate type C RNA virus group
Infectious primate type C viruses have recently been recovered
from several colonies of gibbon apes with various hematopoietic
neoplasms, especially myelogenous and lymphoid leukemias (32), and
from one woolly monkey with a spontaneous fibrosarcoma (a New World
primate) (33,34). GAL V (gibbon ape leukemia virus) and SSV-SSA
V (simian sarcoma virus-simian sarcoma associated virus) spread
from animal to animal under natural conditions and induce tumors
when inoculated into other primates (34-36). These viruses are related
to one another by several immunologic criteria and contain related
RNA genomes (37). Gene sequences homologous to those of the RNAs
of GAL V and SSA V have not been detected in the cellular DNA of
normal primates studied thus far (38, 19). Thus, unlike the baboon
type C virus, these two viruses are not endogenous viruses of primates.
The type C viruses of the GAL V-SSA V group are poorly controlled
by the primate host and appear readily capable of producing neoplastic
disease. Infection by such viruses can cause local epidemics of
lymphoproliferative tumors in infected gibbon colonies (39). The
ability to isolate viruses from gibbons, however, is not restricted
to animals with tumors. Recently, three isolates have been obtained
from the brains of normal gibbons (animals without tumors) from
a single colony in the United States (37). Based on immunologic
assays and interference tests, the group of infectious type C viruses
of primates contains many members, all partially related to one
another. At present, the infectious primate type C viruses can be
classified into four distinct subgroups (see Table 8) based on hybridization
Table VIII: Infectious primate type C
viruses; isolation and partial characterization
which show extensive mismatching of the gene sequences when the
different gibbon isolates were compared to one another and to SSA
V (37). It is probable that additional subgroups will be defined
as new isolates are obtained. In studying the relationships between
the various mammalian type C viruses using nucleic acid hybridization
it was noted that the infectious primate viruses, GAL V and SSA
V, share a significant degree of nucleic acid sequence homology
with endogenous type C viruses from the laboratory mouse, Mus musculus
(40). Several homologous proteins of these two major groups of viruses
also share unique interspecies determinants ( 41 ). These unexpected
findings suggested the possibility that the infectious primate viruses
of the GAL V -SSA V group were derived from endogenous mouse viruses
or from a type C virus of a rodent closely related to the mouse.
Primates can, therefore, possess both endogenous and exogenous type
C viruses. The ease with which type C viruses can be isolated from
an Asian primate, the gibbon, and their relationship to Mus musculus
cellular DNA suggested that an Asian species of Mfus might have
a more closely related endogenous virus. For these reasons, we chose
to study type C viruses from several feral Asian subspecies of Mus
musculus. Ten of thirteen single cell clones of the distantly related
Thai mouse species Mf us caroli are inducible for a xenotropic type
C virus. This virus, unlike the isolates from other Mus musculus
subspecies, was found to be closely related antigenically to a group
of infectious primate type C viruses (gibbon and woolly monkey type
C viruses) and only weakly related to and distinctly different from
previously studied type C viruses of Mus musculus. The polymerase
of the Mus caroli virus is antigenically more similar to the primate
viral enzymes than to the enzymes of all musculus type C viruses
tested (Table 9). It shares cross-reactive p30 antigens, and cross-interferes
with the infectious primate type C viruses ( 42). The p30 protein
of the Muscaroli virus is more closely related antigenically to
viruses of the GAL V -SSA V group than to M us musculus type C viruses.
By immunologic and interference criteria, then, the virus isolated
from Mus caroli cells is unique among the murine viruses characterized
thus far in its close relationship to infectious viruses isolated
from primates. These results lead to the conclusion that
Table IX: Inhibition of viral reverse
transcriptase Activity by antisera to viral polymerases
a group of infectious, type C viruses horizontally transmitted among
primates originated by trans-species infection( s ) of certain primates
(gibbon, woolly monkey, and perhaps other apes and monkeys) by an
endogenous type C virus from Mus caroli or another closely related
species. This trans-species infection appears to be a relatively
recent, perhaps contemporary, event with the viruses not yet being
incorporated into the genomes of the recipient primate species.
Type C RNA viruses and human neoplasia
The studies of type C virogenes in primate populations as described
above are unusually significant: first, they are the first isolates
of type C viruses from primates; second, some of these viruses have
been proven to be oncogenic; third, they provide the closest model
of animal neoplasia for man; and fourth, it is possible that one,
the other, or both of these two primate virus groups (GAL V and
SSA V) may be involved in human neoplasia. Since the horizontally
transmitted primate viruses described above are infectious for and
can cause tumors in primates, the possibility exists that this group
of viruses may be involved in the etiology of human cancer. This
is supported by data obtained using different experimental procedures
in a number of laboratories. An enzyme with biochemical properties
related to those of type C viruses and with antigenic properties
similar to polymerases of the woolly monkey type C virus (SSA V)
and the gibbon ape leukemia virus (GAL V) has been detected in human
acute leukemia cells ( 43, 44 ). The DNA products of endogenous
reactions from the "virus-like" particulate fraction of acute leukemia
cells hybridize preferentially to viral RNA from SSA V and GAL V
(45,46). Using radioimmunoassays, antigens related to the major
structural proteins (p30) of type C viruses have been detected in
peripheral white blood cells from five patients with acute leukemia
(47). These results suggest that viruses of this group, known to
be infectious for and tumorigenic in other primates, may also be
associated with acute leukemia in man. Recently, several laboratories
have reported the isolation of complete infectious type C viruses
from human materials ( 48-51 ). Most information is available on
the isolate designated HL-23, obtained from a cell culture derived
from a woman with acute myelogenous leukemia. It appears to be closely
related to the woolly monkey virus, SSA V (50), and thus may belong
to one of the four previously described subgroups of infectious
primate viruses. A virus closely related to baboon type C viruses
was also isolated from patient HL-23 (52). Since two different type
C viruses also related to the same primate viruses as HL-23 have
recently been found in the human embryo cells described by Panem
et al. ( 49), isolation of one infectious virus from human material
now appears to be an unusual rather than common occurrence. Additional
isolates of HL-23 virus have recently been reported from separate
clinical specimens obtained at different intervals from the same
patient ( 53 ). The significance of these isolations, however, requires
further evaluation. The careful characterization of additional isolates
made by other laboratories from human tissues and cell cultures,
then, is awaited with keen interest. Primates, including man, are
known to contain endogenous type C viral sequences in their genome
which are related to those found in endogenous baboon viruses (16).
Endogenous virogenes may be partially expressed in humans and other
primates as evidenced by the detection of RNA sequences (20), and
antigens related to the p30 proteins (20, 21) of endogenous baboon
viruses. The expression of endogenous viral-related antigens is
found in carcinomas and lymphomas (21) as well as in leukemias (47);
viral p30 antigen expression has also been reported in certain normal
human tissues ( 54 ) . If infectious type C RNA viruses are important
agents in cancer causation in man, it is critical to know how the
viral information is transmitted, normally controlled, and maintained
in the population. Are they contained in an animal reservoir or
do they spread solely from primate to primate? Finding this reservoir(s),
if it exists, provides a chance of disrupting the process. If human
leukemia involves the spread of an infectious agent from individual
to individual as is clearly shown to be the case for cat leukemia
(55) and bovine leukemia (56), then identification of the agent
and its mode of spread would provide one set of approaches to prevention
of the disease. If, on the other hand, activation of genetically
transmitted virus by extrinsic ( chemical and physical agents) as
well as by various intrinsic factors leads to tumor development
and there is no contagious virus involved, the approaches to the
prevention of the disease would be quite different. The endogenous
primate type C virogenes, present in human cells, would appear to
be the more logical candidate virus for involvement in the generality
of human cancer.
Possible normal functions of type C viruses
The presence of genetically transmitted viral genes in so many
vertebrate species and the evidence that they have been conserved
through evolution in several distinct vertebrate lineages suggests
that they may provide normal function(s)
Table X: Possible functions of genetically transmitted virogenes
in normal cells
1. Activation of oncogenic information, while inappropriate in
adult tissue, plays a normal role during differentiation and development.
2. The integrated virus serves to protect the species against
related, more virulent infectious type C viruses.
3. Virus activation, being linked to transformation, protects the
animal by altering the cell membrane. The released virus could alert
the immune system making the transformed cells more susceptible
to immunologic control.
4. They may have had an evolutionary role as conveyors of genetic
information not only within a species but also between species.
Only this group of viruses has been shown to transmit genes between
germ cells of different species under natural conditions.
advantageous to the species carrying them (Table 10). The first
suggested role, derived from studies on the expression of viral
antigens during the course of development, was that such viral expression
during the early stages of differentiation was a normal part of
the developmental process (3). If this were the case, the expression
of cancer genes later in life would be an inappropriate manifestation
of a normal developmental function. If viral genes provide a function
critical for normal development, they clearly would be conserved
during evolution. The acquisition of viral genes by cats from both
primates and rodents, and by pigs from rodents, along with the fact
that they have been maintained for millions of years suggests the
possibility that the newly acquired viral genes, once integrated,
might have been beneficial to the recipient species if they were
able to provide resistance to related, but more virulent viruses.
Animals that successfully integrated the genomes would have been
at a selective advantage relative to those that did not, if the
integrated genome protected against infection, and if infection
led to cancer or other type C viral-mediated diseases. Genes that
provide protection against disease, especially against epidemic
diseases, would be at a strong selective advantage in natural populations.
This may well explain the success of the transmission between species
as described above. For example, in our laboratory we have shown
that those species of the genus Felis, including the domestic cat,
that have acquired primate type C viral genes are resistant to infection
by the endogenous baboon viruses, while those Felis species that
have not acquired the viral information are still susceptible to
baboon viral information. A third possible role for endogenous viruses
arises if viral activation was closely linked to the transformed
state in the cell. Expression of the endogenous virus under natural
circumstances, may be protective on an immunological basis against
cancer, rather than the virus acting as the etiological agent. The
activated virus could alter the cell membrane and thus alert the
host immune system, conveying information as to the number and location
of transformed cells in the body. This possibility is supported
by the observation that transformed cells in culture, whether transformed
spontaneously, by chemical carcinogens, or by other viruses, release
their endogenous type C viruses more readily than do their normal,
untransformed counterparts (57-59). Transformed cells that are releasing
high titers of type C virus have been reported to be much less able
to produce tumors when inoculated into immunocompetent animals of
the same species (60). Partial viral expression where viral antigens
are introduced into the cell surface may be sufficient to alter
its antigenicity and facilitate rejection of these cells. One final
possibility that should be considered is that type C viruses have
played an important evolutionary role as transmitters of genetic
information, not only between cells of an animal, and animals of
a species, but also between species. That viruses can transmit themselves
between the germ cell DNAs of very different species has been established
as a result of experiments in the past year. That they can recombine
with cellular gene sequences and transmit these genes to new cells
of a different species also has been clearly demonstrated (61, 62).
That this transmission of cellular gene information between species
has been a major force in evolution, however, remains a speculation.
This suggestion that viruses may have had a major role in evolution
is not anew one (63). Viruses are unique in that they can serve
to carry information between genetically isolated species. Classical
Darwinian evolution deals with changes which occur within the genetic
information of a species; which can be changed and rearranged by
mutation and selection, duplication and rearrangements, but not
added to from the outside. Viruses, however, offer the possibility
of additions of new gene sequences to a species. The type C viruses
as a group, are uniquely suited for this role since they must incorporate
into the cellular DNA in order to replicate (14) but they do not
kill the cells that they infect. Each time they move from cell to
cell they may carry with them host cell genes providing a means
of communication between cells of different species and different
phyla. They serve to keep a species in contact or in communication
with its neighbors-ecologic neighbors as well as genetic neighbors.
Of course they can transmit information that may disrupt normal
cellular control, and by so doing, lead to the development of cancer
in the individual. Instances of genetic significance, however, occur
when new genes are incorporated into the germ line. From this perspective,
the fact that these viruses cause cancer would then be viewed as
a pathological manifestation of normal processes. While the viral
genes may well be etiologic agents in cancer causation, either as
exogenous or endogenous viruses, and this may be of profound significance
to the affected individuals, these relatively rare and sporadic
cases may not be of great evolutionary significance.
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