Review of Medical Microbiology and Immunology, 13th Edition

43. Tumor Viruses



Malignant Transformation of Cells

Altered Morphology

Altered Growth Control

Altered Cellular Properties

Altered Biochemical Properties

Role of Tumor Viruses In Malignant Transformation

Proviruses & Oncogenes

Outcome of Tumor Virus Infection

Transmission of Tumor Viruses

Human Tumor Viruses

Human T-Cell Lymphotropic Virus

Hepatitis C Virus

Human Papillomavirus

Epstein–Barr Virus

Human Herpesvirus 8

Hepatitis B Virus

Merkel Cell Polyomavirus

Vaccines Against Cancer

Do Animal Tumor Viruses Cause Cancer In Humans?

Animal Tumor Viruses





Self-Assessment Questions

Summaries of Organisms

Practice Questions: USMLE & Course Examinations


Viruses can cause benign or malignant tumors in many species of animals (e.g., frogs, fishes, birds, and mammals). Despite the common occurrence of tumor viruses in animals, only a few viruses are associated with human tumors, and evidence that they are truly the causative agents exists for very few.

Tumor viruses have no characteristic size, shape, or chemical composition. Some are large, and some are small; some are enveloped, and others are naked (i.e., nonenveloped); some have DNA as their genetic material, and others have RNA. The factor that unites all of them is their common ability to cause tumors.

Tumor viruses are at the forefront of cancer research for two main reasons:

(1) They are more rapid, reliable, and efficient tumor producers than either chemicals or radiation. For example, many of these viruses can cause tumors in all susceptible animals in 1 or 2 weeks and can produce malignant transformation in cultured cells in just a few days.

(2) They have a small number of genes compared with a human cell (only three, four, or five for many retroviruses), and hence their role in the production of cancer can be readily analyzed and understood. To date, the genomes of many tumor viruses have been cloned and sequenced and the number of genes and their functions have been determined; all of this has provided important information.


The term malignant transformation refers to changes in the growth properties, shape, and other features of the tumor cell (Table 43–1). Malignant transformation can be induced by tumor viruses not only in animals but also in cultured cells. In culture, the following changes occur when cells become malignantly transformed.

TABLE 43–1 Features of Malignant Transformation


Altered Morphology

Malignant cells lose their characteristic differentiated shape and appear rounded and more refractile when seen in a microscope. The rounding is due to the disaggregation of actin filaments, and the reduced adherence of the cell to the surface of the culture dish is the result of changes in the surface charge of the cell.

Altered Growth Control

(1) Malignant cells grow in a disorganized, piled-up pattern in contrast to normal cells, which have an organized, flat appearance. The term applied to this change in growth pattern in malignant cells is loss of contact inhibition. Contact inhibition is a property of normal cells that refers to their ability to stop their growth and movement upon contact with another cell. Malignant cells have lost this ability and consequently move on top of one another, continue to grow to large numbers, and form a random array of cells.

(2) Malignant cells are able to grow in vitro at a much lower concentration of serum than are normal cells.

(3) Malignant cells grow well in suspension, whereas normal cells grow well only when they are attached to a surface (e.g., a culture dish).

(4) Malignant cells are easily cloned (i.e., they can grow into a colony of cells starting with a single cell), whereas normal cells cannot do this effectively.

(5) Infection of a cell by a tumor virus “immortalizes” that cell by enabling it to continue growing long past the time when its normal counterpart would have died. Normal cells in culture have a lifetime of about 50 generations, but malignantly transformed cells grow indefinitely.

Altered Cellular Properties

(1) DNA synthesis is induced. If cells resting in the G1 phase are infected with a tumor virus, they will promptly enter the S phase (i.e., synthesize DNA and go on to divide).

(2) The karyotype becomes altered (i.e., there are changes in the number and shape of the chromosomes as a result of deletions, duplications, and translocations).

(3) Antigens different from those in normal cells appear. These new antigens can be either virus-encoded proteins, preexisting cellular proteins that have been modified, or previously repressed cellular proteins that are now being synthesized. Some new antigens are on the cell surface and elicit either circulating antibodies or a cell-mediated response that can kill the tumor cell. These new antigens are the recognition sites for immune surveillance against tumor cells.

(4) Agglutination by lectins is enhanced. Lectins are plant glycoproteins that bind specifically to certain sugars on the cell membrane surface (e.g., wheat germ agglutinin). The increased agglutination of malignant cells may be due to the clustering of existing receptor sites rather than to the synthesis of new ones.

Altered Biochemical Properties

(1) Levels of cyclic adenosine monophosphate (AMP) are reduced in malignant cells. Addition of cyclic AMP will cause malignant cells to revert to the appearance and growth properties of normal cells.

(2) Malignant cells secrete more plasminogen activator than do normal cells. This activator is a protease that converts plasminogen to plasmin, the enzyme that dissolves the fibrin clot.

(3) Increased anaerobic glycolysis leads to increased lactic acid production (Warburg effect). The mechanism for this change is unknown.

(4) There is a loss of high-molecular-weight glycoprotein called fibronectin. The effect of this loss is unknown.

(5) There are changes in the sugar components of glycoproteins and glycolipids in the membranes of malignant cells.


Malignant transformation is a permanent change in the behavior of the cell. Must the viral genetic material be present and functioning at all times, or can it alter some cell component and not be required subsequently? The answer to this question was obtained by using a temperature-sensitive mutant of Rous sarcoma virus. This mutant has an altered transforming gene that is functional at the low, permissive temperature (35°C) but not at the high, restrictive temperature (39°C). When chicken cells were infected at 35°C they transformed as expected, but when incubated at 39°C, they regained their normal morphology and behavior within a few hours. Days or weeks later, when these cells were returned to 35°C, they recovered their transformed phenotype. Thus continued production of some functional virus-encoded protein is required for the maintenance of the transformed state.

Although malignant transformation is a permanent change, revertants to normality do appear, albeit rarely. In the revertants studied, the viral genetic material remains integrated in cellular DNA, but changes in the quality and quantity of the virus-specific RNA occur.


The two major concepts of the way viral tumorigenesis occurs are expressed in the terms provirus and oncogene. These contrasting ideas address the fundamental question of the source of the genes for malignancy.

(1) In the provirus model, the genes enter the cell at the time of infection carried by the tumor virus.

(2) In the oncogene model, the genes for malignancy are already present in all cells of the body by virtue of being present in the initial sperm and egg. These oncogenes encode proteins that encourage cell growth (e.g., fibroblast growth factor). In the oncogene model, carcinogens such as chemicals, radiation, and tumor viruses activate cellular oncogenes to overproduce these growth factors. This initiates inappropriate cell growth and malignant transformation (Figure 43–1).


FIGURE 43–1 Effect of cellular oncogenes and tumor suppressor genes on the cell cycle. The oncoproteins encoded by cellular oncogenes activate the cell cycle by allowing passage from the G1 phase into the S phase. The proteins encoded by tumor suppressor genes, notably p53 and RB, inhibit the cell cycle in the G1 phase. Inactivation of these proteins activates the cell cycle by allowing passage from the G1 phase into the S phase. G1, gap 1; G2, gap 2; M, mitosis; S, synthesis of DNA. (Modified with permission from Murray RK et al. Harper’s Illustrated Biochemistry. 29th ed. New York: McGraw-Hill, 2012.)

Both proviruses and oncogenes may play a role in malignant transformation. Evidence for the provirus mode consists of finding copies of viral DNA integrated into cell DNA only in cells that have been infected with the tumor virus. The corresponding uninfected cells have no copies of the viral DNA.

1. Role of Cellular Oncogenes in Tumorigenesis

The first direct evidence that oncogenes exist in normal cells was based on results of experiments in which a DNA copy of the onc gene of the chicken retrovirus Rous sarcoma virus was used as a probe. DNA in normal chicken embryonic cells hybridized to the probe, indicating that the cells contain a gene homologous to the viral gene. It is hypothesized that the cellular oncogenes may be the precursors of viral oncogenes. Proto-oncogenes are the normal precursors of the cellular oncogenes. Proto-oncogenes encode normal cellular proteins and are under regulatory control. Cellular oncogenes have acquired mutations that cause them to escape regulatory control and overproduce altered proteins. Figure 43–2 shows the functions of important oncoproteins encoded by the cellular oncogenes.


FIGURE 43–2 Functions of cellular oncoproteins. Cellular oncogenes encode proteins with a variety of functions that are shown in the figure. These oncoproteins activate the cell cycle and cause cell to grow in an unregulated manner. Used with permission from Murray RK et al. Harper’s Illustrated Biochemistry. 29th ed. New York: McGraw-Hill, 2012.)

Although cellular oncogenes and viral oncogenes are similar, they are not identical. They differ in base sequence at various points; and cellular oncogenes have exons and introns, whereas viral oncogenes do not. It seems likely that viral oncogenes were acquired by incorporation of cellular oncogenes into retroviruses lacking these genes. Retroviruses can be thought of as transducing agents, carrying oncogenes from one cell to another. (See Chapter 4 for a discussion of transduction).

Since this initial observation, more than 20 cellular oncogenes have been identified by using either the Rous sarcoma virus DNA probe or probes made from other viral oncogenes. Table 43–2 describes the function of several important cellular oncogenes and their relationship to various human cancers. Many cells contain several different cellular oncogenes. In addition, the same cellular oncogenes have been found in species as diverse as fruit flies, rodents, and humans. Such conservation through evolution suggests a normal physiologic function for these genes. Some are known to be expressed during normal embryonic development.

TABLE 43–2 Examples of Cellular Oncogenes Involved in Human Cancer


A marked diversity of viral oncogene function has been found. Some, such as the src gene, encode a protein kinase that specifically phosphorylates the amino acid tyrosine, in contrast to the commonly found protein kinase of cells, which preferentially phosphorylates serine.

Other oncogenes have a base sequence almost identical to that of the gene for certain cellular growth factors (e.g., epidermal growth factor). Several proteins encoded by oncogenes have their effect at the cell membrane (e.g., the ras oncogene encodes a G protein), whereas some act in the nucleus by binding to DNA (e.g., the myc oncogene encodes a transcription factor). These observations suggest that growth control is a multistep process and that carcinogenesis can be induced by affecting one or more of several steps.

On the basis of the known categories of oncogenes, the following model of growth control can be constructed. After a growth factor binds to its receptor on the cell membrane, membrane-associated G proteins and tyrosine kinases are activated. These, in turn, interact with cytoplasmic proteins or produce second messengers, which are transported to the nucleus and interact with nuclear factors. DNA synthesis is activated, and cell division occurs. Overproduction or inappropriate expression of any of the preceding factors in boldface type can result in malignant transformation.

Note that not all tumor viruses of the retrovirus family contain onc genes. How do these viruses cause malignant transformation? It appears that the DNA copy of the viral RNA integrates near a cellular oncogene, causing a marked increase in its expression. This process is called insertional mutagenesisOverexpression of the cellular oncogene may play a key role in malignant transformation by these viruses.

Although it has been demonstrated that viral oncogenes can cause malignant transformation, it has not been directly shown that cellular oncogenes can do so. However, as described in Table 43–3, the following evidence suggests that they do:

TABLE 43–3 Evidence That Cellular Oncogenes (c-onc) Can Cause Tumors


(1) DNA-containing cellular oncogenes isolated from certain tumor cells can transform normal cells in culture. When the base sequence of these “transforming” cellular oncogenes was analyzed, it was found to have a single base change from the normal cellular oncogene (i.e., it had mutated). In several tumor cell isolates, the altered sites in the gene are the same.

(2) In certain tumors, characteristic translocations of chromosomal segments can be seen. In Burkitt’s lymphoma cells, a translocation occurs that moves a cellular oncogene (c-myc) from its normal site on chromosome 8 to a new site adjacent to an immunoglobulin heavy chain gene on chromosome 14. This shift enhances expression of the c-myc gene.

In chronic myelogenous leukemia (CML) cells, a truncated chromosome called a “Philadelphia” chromosome is seen. This chromosome has a characteristic translocation that results in the overexpression of the bcr-abl oncogene that encodes a tyrosine kinase. Increased kinase activity increases the rate of cell division and inhibits DNA repair resulting in leukemia. Drugs that inhibit this kinase, such as imatinib (Gleevec), induce a prolonged remission and are well tolerated.

(3) Some tumors have multiple copies of the cellular oncogenes, either on the same chromosome or on multiple tiny chromosomes. The amplification of these genes results in overexpression of their mRNA and proteins.

(4) Insertion of the DNA copy of the retroviral RNA (proviral DNA) near a cellular oncogene stimulates expression of the c-onc gene.

(5) Certain cellular oncogenes isolated from normal cells can cause malignant transformation if they have been modified to be overexpressed within the recipient cell.

In summary, two different mechanisms—mutation and increased expression—appear to be able to activate the quiescent “proto-oncogene” into a functioning oncogene capable of transforming a cell. Cellular oncogenes provide a rationale for carcinogenesis by chemicals and radiation (e.g., a chemical carcinogen might act by enhancing the expression of a cellular oncogene). Furthermore, DNA isolated from cells treated with a chemical carcinogen can malignantly transform other normal cells. The resulting tumor cells contain cellular oncogenes from the chemically treated cells, and these genes are expressed with high efficiency.

2. Role of Cellular Tumor Suppressor Genes in Tumorigenesis

There is another mechanism of carcinogenesis involving cellular genes, namely, mutation of a tumor suppressor gene (Figure 43–1). A well-documented example is the retinoblastoma susceptibility gene, which normally acts as a suppressor of retinoblastoma formation. When both alleles of this antioncogene are mutated (made nonfunctional), retinoblastoma occurs. Human papillomavirus and SV40 virus produce a protein that binds to and inactivates the protein encoded by the retinoblastoma gene. Human papillomavirus also produces a protein that inactivates the protein encoded by the p53 gene, another tumor suppressor gene in human cells. The p53 gene encodes a transcription factor that activates the synthesis of a second protein, which blocks the cyclin-dependent kinases required for cell division to occur. The p53 protein also promotes apoptosis of cells that have sustained DNA damage or contain activated cellular oncogenes. Apoptosis-induced death of these cells has a “tumor-suppressive” effect by killing those cells destined to become cancerous.

Inactivation of tumor suppressor genes appears likely to be an important general mechanism of viral oncogenesis. Tumor suppressor genes are involved in the formation of other cancers as well (e.g., breast and colon carcinomas and various sarcomas). For example, in many colon carcinomas, two genes are inactivated, the p53 gene and the DCC (deleted in colon carcinoma) gene. Table 43–4 lists several important tumor suppressor genes and their relationship to various human cancers. More than half of human cancers have a mutated p53 gene in the DNA of malignant cells.

TABLE 43–4 Examples of Tumor Suppressor Genes Involved in Human Cancer


3. Role of Cellular Micro-RNA Genes in Tumorigenesis

Micro-RNA genes do not encode proteins but rather exert their regulatory effect by being transcribed into micro-RNA that can bind to sequences in mRNA and prevent that mRNA from being translated into proteins. For example, there are micro-RNAs that bind to (“silence”) mRNA transcribed from a tumor suppressor gene. As a result, the tumor suppressor protein is not synthesized, which enhances the likelihood of tumorigenesis.


The outcome of tumor virus infection is dependent on the virus and the type of cell. Some tumor viruses go through their entire replicative cycle with the production of progeny virus, whereas others undergo an interrupted cycle, analogous to lysogeny, in which the proviral DNA is integrated into cellular DNA and limited expression of proviral genes occurs. Therefore, malignant transformation does not require that progeny virus be produced. Rather, all that is required is the expression of one or, at most, a few viral genes. Note, however, that some tumor viruses transform by inserting their proviral DNA in a manner that activates a cellular oncogene.

In most cases, the DNA tumor viruses such as the papovaviruses transform only cells in which they do not replicate. These cells are called “nonpermissive” because they do not permit viral replication. Cells of the species from which the DNA tumor virus was initially isolated are “permissive” (i.e., the virus replicates and usually kills the cells, and no tumors are formed). For example, SV40 virus replicates in the cells of the African green monkey (its species of origin) and causes a cytopathic effect but no tumors. However, in rodent cells, the virus does not replicate, expresses only its early genes, and causes malignant transformation. In the “nonproductive” transformed cell, the viral DNA is integrated into the host chromosome and remains there through subsequent cell divisions. The underlying concept applicable to both DNA and RNA tumor viruses is that only viral gene expression, not replication of the viral genome or production of progeny virus, is required for transformation.

The essential step required for a DNA tumor virus (e.g., SV40 virus) to cause malignant transformation is expression of the “early” genes of the virus (Table 43–5). (The early genes are those expressed prior to the replication of the viral genetic material.) These required early genes produce a set of early proteins called T antigens.1

TABLE 43–5 Viral Oncogenes


The large T antigen, which is both necessary and sufficient to induce transformation, binds to SV40 virus DNA at the site of initiation of viral DNA synthesis. This is compatible with the finding that the large T antigen is required for the initiation of cellular DNA synthesis in the virus-infected cell. Biochemically, large T antigen has protein kinase and adenosine triphosphate (ATPase) activity. Almost all of the large T antigen is located in the cell nucleus, but some of it is in the outer cell membrane. In that location, it can be detected as a transplantation antigen called tumor-specific transplantation antigen (TSTA). TSTA is the antigen that induces the immune response against the transplantation of virally transformed cells. Relatively little is known about the SV40 virus small T antigen, except that if it is not synthesized, the efficiency of transformation decreases. In polyomavirus-infected cells, the middle T antigen plays the same role as the SV40 virus large T antigen.

In RNA tumor virus–infected cells, this required gene has one of several different functions, depending on the retrovirus. The oncogene of Rous sarcoma virus and several other viruses codes for a protein kinase that phosphorylates tyrosine. Some viruses have a gene for a factor that regulates cell growth (e.g., epidermal growth factor or platelet-derived growth factor), and still others have a gene that codes for a protein that binds to DNA. The conclusion is that normal growth control is a multistep process that can be affected at any one of several levels. The addition of a viral oncogene perturbs the growth control process, and a tumor cell results.

The viral genetic material remains stably integrated in host cell DNA by a process similar to lysogeny. In the lysogenic cycle, bacteriophage DNA becomes stably integrated into the bacterial genome. The linear DNA genome of the temperate phage, lambda, forms a double-stranded circle within the infected cell and then covalently integrates into bacterial DNA (Table 43–6). A repressor is synthesized that prevents transcription of most of the other lambda genes. Similarly, the double-stranded circular DNA of the DNA tumor virus covalently integrates into eukaryotic-cell DNA, and only early genes are transcribed. Thus far, no repressor has been identified in any DNA tumor virus–infected cell. With RNA tumor viruses (retroviruses), the single-stranded linear RNA genome is transcribed into a double-stranded linear DNA that integrates into cellular DNA. In summary, despite the differences in their genomes and in the nature of the host cells, these viruses go through the common pathway of a double-stranded DNA intermediate followed by covalent integration into cellular DNA and subsequent expression of certain genes.

TABLE 43–6 Lysogeny as a Model for the Integration of Tumor Viruses


Just as a lysogenic bacteriophage can be induced to enter the replicative cycle by ultraviolet radiation and certain chemicals, tumor viruses can be induced by several mechanisms. Induction is one of the approaches used to determine whether tumor viruses are present in human cancer cells (e.g., human T-cell lymphotropic virus was discovered by inducing the virus from leukemic cells with iododeoxyuridine).

Three techniques have been used to induce tumor viruses to replicate in the transformed cells:

(1) The most frequently used method is the addition of nucleoside analogues (e.g., iododeoxyuridine). The mechanism of induction by these analogues is uncertain.

(2) The second method involves fusion with “helper” cells (i.e., the transformed, nonpermissive cell is fused with a permissive cell) in which the virus undergoes a normal replicative cycle. Within the heterokaryon (a cell with two or more nuclei that is formed by the fusion of two different cell types), the tumor virus is induced and infectious virus is produced. The mechanism of induction is unknown.

(3) In the third method, helper viruses provide a missing function to complement the integrated tumor virus. Infection with the helper virus results in the production of both the integrated tumor virus and the helper virus.

The process of rescuing tumor viruses from cells revealed the existence of endogenous viruses. Treatment of normal, uninfected embryonic cells with nucleoside analogues resulted in the production of retroviruses. Retroviral DNA is integrated within the chromosomal DNA of all cells and serves as the template for viral replication. This proviral DNA probably arose by retrovirus infection of the germ cells of some prehistoric ancestor.

Endogenous retroviruses, which have been rescued from the cells of many species (including humans), differ depending on the species of origin. Endogenous viruses are xenotropic (xeno means foreign; tropism means to be attracted to; i.e., they infect cells of other species more efficiently than they infect the cells of the species of origin). Entry of the endogenous virus into the cell of origin is limited as a result of defective viral envelope–cell receptor interaction. Although they are retroviruses, most endogenous viruses are not tumor viruses (i.e., only a few cause leukemia).


Tumor virus transmission in experimental animals can occur by two processes, vertical and horizontal. Vertical transmission indicates movement of the virus from mother to newborn offspring, whereas horizontal transmission describes the passage of virus between animals that do not have a mother–offspring relationship. Vertical transmission occurs by three methods: (1) the viral genetic material is in the sperm or the egg; (2) the virus is passed across the placenta; and (3) the virus is transmitted in the breast milk.

When vertical transmission occurs, exposure to the virus early in life can result in tolerance to viral antigens and, as a consequence, the immune system will not eliminate the virus. Large amounts of virus are produced, and a high frequency of cancer occurs. In contrast, when horizontal transmission occurs, the immunocompetent animal produces antibody against the virus, and the frequency of cancer is low. If an immunocompetent animal is experimentally made immunodeficient, the frequency of cancer increases greatly.

Horizontal transmission probably does not occur in humans; those in close contact with cancer patients (e.g., family members and medical personnel) do not have an increased frequency of cancer. There have been “outbreaks” of leukemia in several children at the same school, but these have been interpreted statistically to be random, rare events that happen to coincide.


There are seven known human tumor viruses (Table 43–7). Two are RNA viruses, namely human T-cell lymphotropic virus and hepatitis C virus. The other five are DNA viruses, namely human papillomavirus, Epstein–Barr virus, human herpesvirus 8 (Kaposi’s sarcoma virus), hepatitis B virus, and Merkel cell polyomavirus.

TABLE 43–7 Varieties of Tumor Viruses


1. RNA Tumor Viruses

Human T-Cell Lymphotropic Virus

There are two human T-cell lymphotropic virus (HTLV) isolates so far, HTLV-1 and HTLV-2, both of which are associated with leukemias and lymphomas. HTLV-1 was isolated in 1980 from the cells of a patient with a cutaneous T-cell lymphoma. Its RNA and proteins are different from those of all other retroviruses. In addition to cancer, HTLV is the cause of tropical spastic paraparesis, an autoimmune disease in which progressive weakness of the legs occurs. (Additional information regarding HTLV can be found in Chapter 39.)

HTLV-1 may cause cancer by a mechanism different from that of other retroviruses. It has no viral oncogene. Rather, it has two special genes (in addition to the standard retroviral genes gag, pol, and env) called tax and rex that play a role in oncogenesis by regulating mRNA transcription and translation. The Tax protein has two activities: (1) it acts on the viral long terminal repeat (LTR) sequences to stimulate viral mRNA synthesis; and (2) it induces nuclear factor- κB (NF-κB), which stimulates the production of interleukin-2 (IL-2) and the IL-2 receptor. The increase in levels of IL-2 and its receptor stimulates the T cells to continue growing, thus increasing the likelihood that the cells will become malignant. The Rex protein determines which viral mRNAs can exit the nucleus and enter the cytoplasm to be translated.

HTLV-1 is not an endogenous virus (i.e., proviral DNA corresponding to its RNA genome is not found in normal human cell DNA). It is an exogenously acquired virus because its proviral DNA is found only in the DNA of the malignant lymphoma cells. It infects CD4-positive T cells preferentially and will induce malignant transformation in these cells in vitro. Some (but not all) patients with T-cell lymphomas have antibodies against the virus, indicating that it may not be the cause of all T-cell lymphomas. Antibodies against the virus are not found in the general population, indicating that infection is not widespread.

Transmission occurs primarily by breast feeding, by sexual contact, and by exchange of contaminated blood (e.g., in transfusions and intravenous drug users). In the United States, blood for transfusions is screened for antibodies to HTLV-1 and HTLV-2 and discarded if positive. In recent years, HTLV-1 and HTLV-2 were found in equal frequency in donated blood. Serologic tests for HTLV do not cross-react with human immunodeficiency virus (HIV).

At about the same time that HTLV-1 was found, a similar virus was isolated from malignant T cells in Japan. In that country, a clustering of cases in the rural areas of the west coast of Kyushu was found. Antibodies in the sera of leukemic individuals and in the sera of 25% of the normal population of Kyushu react with the Japanese isolate and with HTLV-1. (Only a small fraction of infected individuals contract leukemia, indicating that HTLV infection alone is insufficient to cause cancer.) In addition, HTLV-1 is endemic in some areas of Africa and on several Caribbean islands, as shown by the high frequency of antibodies. The number of people with positive antibody titers in the United States is quite small, except in certain parts of the southeastern states.

HTLV-2 has 60% genetic homology with HTLV-1. Like HTLV-1, it is transmitted primarily by blood and semen and infects CD4-positive cells. Routine serologic tests do not distinguish between HTLV-1 and HTLV-2; therefore, other techniques (e.g., polymerase chain reaction) are required.

Hepatitis C Virus

Chronic infection with hepatitis C virus (HCV), like hepatitis B virus (HBV), also predisposes to hepatocellular carcinoma. HCV is an RNA virus that has no oncogene and forms no DNA intermediate during replication. It does cause chronic hepatitis, which seems likely to be the main predisposing event. (Additional information regarding HCV can be found in Chapter 41.)

2. DNA Tumor Viruses

Human Papillomavirus

Human papillomavirus (HPV) is one of the two viruses definitely known to cause tumors in humans. Papillomas (warts) are benign but can progress to form carcinomas, especially in an immunocompromised person. HPV primarily infects keratinizing or mucosal squamous epithelium. (Additional information regarding HPV can be found in Chapter 38.)

Papillomaviruses are DNA nucleocapsid viruses with double-stranded, circular, supercoiled DNA and an icosahedral nucleocapsid. Carcinogenesis by HPV involves two proteins encoded by HPV genes E6 and E7 that interfere with the activity of the proteins encoded by two tumor suppressor genes, p53 and Rb (retinoblastoma), found in normal cells. In cancer cells, the viral DNA is integrated into the cellular DNA, and the E6 and E7 proteins are produced.

There are at least 100 different types of HPV, many of which cause distinct clinical entities. For example, HPV-1 through HPV-4 cause plantar warts on the soles of the feet, whereas HPV-6 and HPV-11 cause anogenital warts (condylomata acuminata) and laryngeal papillomas. Certain types of HPV, especially types 16 and 18, are implicated as the cause of carcinoma of the cervix, penis, and anus.

Epstein–Barr Virus

Epstein–Barr virus (EBV) is a herpesvirus that was isolated from the cells of an East African individual with Burkitt’s lymphoma. EBV, the cause of infectious mononucleosis, transforms B lymphocytes in culture and causes lymphomas in marmoset monkeys. It is also associated with nasopharyngeal carcinoma, a tumor that occurs primarily in China, and with thymic carcinoma and B-cell lymphoma in the United States. However, cells from Burkitt’s lymphoma patients in the United States show no evidence of EBV infection. (Additional information regarding EBV can be found in Chapter 37.)

Cells isolated from East African individuals with Burkitt’s lymphoma contain EBV DNA and EBV nuclear antigen. Only a small fraction of the many copies of EBV DNA is integrated; most viral DNA is in the form of closed circles in the cytoplasm.

The difficulty in proving that EBV is a human tumor virus is that infection by the virus is widespread but the tumor is rare. The current hypothesis is that EBV infection induces B cells to proliferate, thus increasing the likelihood that a second event (e.g., activation of a cellular oncogene) will occur. In Burkitt’s lymphoma cells, a cellular oncogene, c-myc, which is normally located on chromosome 8, is translocated to chromosome 14 at the site of immunoglobulin heavy chain genes. This translocation brings the c-myc gene in juxtaposition to an active promoter, and large amounts of c-myc RNA are synthesized. It is known that the c-myc oncogene encodes a transcription factor, but the role of this factor in oncogenesis is uncertain.

Human Herpesvirus 8

Human herpesvirus 8 (HHV-8), also known as Kaposi’s sarcoma–associated herpesvirus (KSHV), causes Kaposi’s sarcoma (KS). KS is a malignancy of vascular endothelial cells that contains many spindle-shaped cells and erythrocytes. It is the most common cancer in patients with acquired immunodeficiency syndrome (AIDS). KSHV is transmitted both sexually and by saliva. A protein encoded by KSHV called latency-associated nuclear antigen (LANA) inactivates RB and p53 tumor suppressor proteins, which causes malignant transformation of the endothelial cells. (Additional information regarding HHV-8 can be found in Chapter 37.)

Hepatitis B Virus

HBV infection is significantly more common in patients with primary hepatocellular carcinoma (hepatoma) than in control subjects. This relationship is striking in areas of Africa and Asia, where the incidence of both HBV infection and hepatoma is high. Chronic HBV infection commonly causes cirrhosis of the liver; these two events are the main predisposing factors to hepatoma. Part of the HBV genome is integrated into cellular DNA in malignant cells. However, no HBV gene has been definitely implicated in oncogenesis. The integration of HBV DNA may cause insertional mutagenesis, resulting in the activation of a cellular oncogene. In addition, the HBx protein may play a role because it inhibits the p53 tumor suppressor protein. (Additional information regarding HBV can be found in Chapter 41.)

Merkel Cell Polyomavirus

Merkel cell polyomavirus (MCPV) causes a carcinoma of Merkel cells in the skin. (Merkel cells are neuroreceptors for pressure and touch.) The carcinoma occurs most often on skin exposed to the sun such as the face and neck. Immunosuppressed individuals and the elderly are predisposed to this cancer.

Members of the polyomavirus family are small, nonenveloped, double-stranded DNA viruses known to cause cancer in animals (see later section on animal tumor viruses). Infection with MCPV is common as indicated by the presence of antibody to the virus in many healthy blood donors. The mode of transmission is uncertain.

In carcinoma cells, the DNA of MCPV is integrated into cell DNA. The gene for the large T antigen is mutated so the virus cannot replicate but the T antigen continues to be synthesized. The T antigen causes the cell to become malignant by inhibiting tumor suppressor proteins such as p53 and RB. Because MCPV does not replicate in the carcinoma cells, patients are not infectious to others.

Diagnosis is made by pathologic analysis of surgical specimens. There is no virus-based laboratory test clinically available. There is no antiviral drug or vaccine available. Prevention involves reducing sun exposure, use of sunscreen, and frequent skin examinations to detect the cancer before it metastasizes.


There are two vaccines designed to prevent human cancer: the HBV vaccine and the HPV vaccine. The widespread use of the HBV vaccine in Asia has significantly reduced the incidence of hepatocellular carcinoma. The vaccine against HPV, the cause of carcinoma of the cervix, was approved for use in the United States in 2006.


There is no evidence that animal tumor viruses cause tumors in humans. In fact, the only available information suggests that they do not, because (1) people who were inoculated with poliovirus vaccine contaminated with SV40 virus have no greater incidence of cancers than do uninoculated controls, (2) soldiers inoculated with yellow fever vaccine contaminated with avian leukemia virus do not have a high incidence of tumors, and (3) members of families whose cats have died of leukemia caused by feline leukemia virus show no increase in the occurrence of leukemia over control families. Note, however, that some human tumor cells, namely, non-Hodgkin’s lymphoma, contain SV40 DNA, but the relationship of that DNA to malignant transformation is uncertain.


1. RNA Tumor Viruses

RNA tumor viruses have been isolated from a large number of species, namely, snakes, birds, and mammals, including nonhuman primates. The important RNA tumor viruses are listed in Table 43–7. They are important because of their ubiquity, their ability to cause tumors in the host of origin, their small number of genes, and the relationship of their genes to cellular oncogenes (see page 350).

These viruses belong to the retrovirus family (the prefix retro means reverse), so named because a reverse transcriptase is located in the virion. This enzyme transcribes the genome RNA into double-stranded proviral DNA and is essential to their replication. The viral genome consists of two identical molecules of positive-strand RNA. Each molecule has a molecular weight of approximately 2 × 106 (these are the only viruses that are diploid [i.e., have two copies of their genome in the virion]). The two molecules are hydrogen-bonded together by complementary bases located near the 5´ end of both RNA molecules. Also bound near the 5´ end of each RNA is a transfer RNA (tRNA) that serves as the primer2 for the transcription of the RNA into DNA.

The icosahedral capsid is surrounded by an envelope with glycoprotein spikes. Some internal capsid proteins are group-specific antigens, which are common to retroviruses within a species. There are three important morphologic types of retroviruses, labeled B, C, and D, depending primarily on the location of the capsid or core. Most of the retroviruses are C-type particles, but mouse mammary tumor virus is a B-type particle, and HIV, the cause of AIDS, is a D-type particle.

The gene sequence of the RNA of a typical avian sarcoma virus is gag, pol, env, and src. The nontransforming retroviruses have three genes; they are missing src. The gag region codes for the group-specific antigens, the pol gene codes for the reverse transcriptase, the env gene codes for the two envelope spike proteins, and the src gene codes for the protein kinase. In other oncogenic retroviruses, such as HTLV-1, there is a fifth coding region (the tax gene) near the 3´ end, which encodes a protein that enhances viral transcription.

The sequences at the 5´ and 3´ ends function in the integration of the proviral DNA and in the transcription of mRNA from the integrated proviral DNA by host cell RNA polymerase II. At each end is a sequence3 called an LTR that is composed of several regions, one of which, near the 5´ end, is the binding site for the primer tRNA.

After infection of the cell by a retrovirus, the following events occur: Using the genome RNA as the template, the reverse transcriptase (RNA-dependent DNA polymerase) synthesizes double-stranded proviral DNA. The DNA then integrates into cellular DNA. Integration of the proviral DNA is an obligatory step, but there is no specific site of integration. Insertion of the viral LTR can enhance the transcription of adjacent host cell genes. If this host gene is a cellular oncogene, malignant transformation may result. This explains how retroviruses without viral oncogenes can cause transformation.

2. DNA Tumor Viruses


The two best-characterized oncogenic papovaviruses are polyomavirus and SV40 virus. Polyomavirus (poly means many; oma means tumor) causes a wide variety of histologically different tumors when inoculated into newborn rodents. Its natural host is the mouse. SV40 virus, which was isolated from normal rhesus monkey kidney cells, causes sarcomas in newborn hamsters.

Polyomavirus and SV40 virus share many chemical and biologic features (e.g., double-stranded, circular, supercoiled DNA of molecular weight 3 × 106 and a 45-nm icosahedral nucleocapsid). However, the sequence of their DNA and the antigenicity of their proteins are quite distinct. Both undergo a lytic (permissive) cycle in the cells of their natural hosts, with the production of progeny virus. However, when they infect the cells of a heterologous species, the nonpermissive cycle ensues, no virus is produced, and the cell is malignantly transformed.

In the transformed cell, the viral DNA integrates into the cell DNA, and only early proteins are synthesized. Some of these proteins (e.g., the T antigens described on page 353) are required for induction and maintenance of the transformed state.

JC virus, a human papovavirus, is the cause of progressive multifocal leukoencephalopathy (see Chapter 44). It also causes brain tumors in monkeys and hamsters. There is no evidence that it causes human cancer.


Some human adenoviruses, especially serotypes 12, 18, and 31, induce sarcomas in newborn hamsters and transform rodent cells in culture. There is no evidence that these viruses cause tumors in humans, and no adenoviral DNA has been detected in the DNA of any human tumor cells.

Adenoviruses undergo both a permissive cycle in some cells and a nonpermissive, transforming cycle in others. The linear genome DNA circularizes within the infected cell, but—in contrast to the papovaviruses, whose entire genome integrates—only a small region (10%) of the adenovirus genome does so; yet transformation still occurs. This region codes for several proteins, one of which is the T (tumor) antigen. Adenovirus T antigen is required for transformation and is antigenically distinct from the polyomavirus and SV40 virus T antigens.


Several animal herpesviruses are known to cause tumors. Four species of herpesviruses cause lymphomas in nonhuman primates. Herpesviruses saimiri and ateles induce T-cell lymphomas in New World monkeys, and herpesviruses pan and papio transform B lymphocytes in chimpanzees and baboons, respectively.

A herpesvirus of chickens causes Marek’s disease, a contagious, rapidly fatal neurolymphomatosis. Immunization of chickens with a live, attenuated vaccine has resulted in a considerable decrease in the number of cases. A herpesvirus is implicated as the cause of kidney carcinomas in frogs.


Two poxviruses cause tumors in animals; these are the fibroma–myxoma virus, which causes fibromas or myxomas in rabbits and other animals, and Yaba monkey tumor virus, which causes benign histiocytomas in animals and human volunteers. Little is known about either of these viruses.


1. Regarding viruses that play a role in human carcinogenesis, which one of the following statements is the most accurate?

(A) Epstein–Barr virus is implicated as the cause of nasopharyngeal carcinoma primarily in Asia, where it is transmitted by mosquitoes in rural areas.

(B) Evidence for hepatitis C virus (HCV) as a cause of hepatocellular carcinoma includes finding a DNA copy of the HCV genome integrated into the DNA of hepatocytes.

(C) Hepatitis B virus is implicated as the cause of hepatocellular carcinoma because countries with a high incidence of chronic hepatitis B also have a high incidence of hepatocellular carcinoma.

(D) Human T-cell leukemia virus is a retrovirus that was found associated with leukemia in Japan but is not found in the United States.

2. Regarding the oncogenes of DNA tumor viruses, which one of the following is most accurate?

(A) They encode protein kinases that phosphorylate p53 protein.

(B) They interact with cellular proto-oncogenes and activate them.

(C) They encode cellular growth factors that activate S-phase DNA synthesis.

(D) They encode proteins that bind to the proteins encoded by tumor suppressor genes.

3. Regarding the main mechanism by which oncogenic retroviruses cause malignant transformation, which one of the following is most accurate?

(A) They cause point mutations in cellular regulatory genes.

(B) They carry the genes for proteins that act as cellular growth factors.

(C) They synthesize a protein that inhibits the action of the cellular p53 protein.

(D) They encode a recombinase that causes translocation of certain chromosomes.

(E) They encode a DNA polymerase that increases the rate of cellular DNA synthesis.


1. (C)

2. (D)

3. (B)


Brief summaries of the organisms described in this chapter begin on page 648. Please consult these summaries for a rapid review of the essential material.


Questions on the topics discussed in this chapter can be found in the Clinical Virology section of PART XIII: USMLE (National Board) Practice Questions starting on page 703. Also see PART XIV: USMLE (National Board) Practice Examination starting on page 731.

1In SV40 virus–infected cells, two T antigens, large (molecular weight [MW] 100,000) and small (MW 17,000), are produced, whereas in polyomavirus-infected cells, three T antigens, large (MW 90,000), middle (MW 60,000), and small (MW 22,000), are made. Other tumor viruses such as adenoviruses also induce T antigens, which are immunologically distinct from those of the two papovaviruses

2The purpose of the primer tRNA is to act as the point of attachment for the first deoxynucleotide at the start of DNA synthesis. The primers are normal-cell tRNAs that are characteristic for each retrovirus.

3 The length of the sequence varies from 250 to 1200 bases, depending on the virus.

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