There are seven known human tumor viruses (Table 43–7). Two are RNA viruses, namely, human T-cell lymphotropic virus and hepatitis C virus (HCV). The other five are DNA viruses, namely, HPV, Epstein–Barr virus (EBV), human herpesvirus 8 (HHV-8) (Kaposi’s sarcoma [KS] virus), hepatitis B virus (HBV), and Merkel cell polyomavirus (MCPV).
Table 43–7Varieties of Tumor Viruses ||Download (.pdf) Table 43–7 Varieties of Tumor Viruses
|Genome Nucleic Acid ||Virus Family ||Human Tumor Viruses ||Animal Tumor Viruses |
|1. RNA || |
Human T-cell leukemia virus
Hepatitis C virus
|Sarcoma, leukemia, and carcinoma viruses in many avian and mammalian species |
|2. DNA ||Papillomavirus ||Human papillomavirus ||Papillomaviruses of many mammals |
|Herpesvirus ||Epstein–Barr virus; human herpesvirus 8 (Kaposi’s sarcoma-associated virus) ||Herpesvirus saimiri causes lymphomas in monkeys; Marek’s disease virus of chickens |
|Hepadnavirus ||Hepatitis B virus ||Hepatitis viruses of ducks and squirrels |
|Polyomavirus ||Merkel cell polyomavirus ||Polyomavirus and SV40 virus cause various cancers in rodents |
|Adenovirus || ||Human adenovirus serotypes 12, 18, and 31 cause sarcomas in rodents |
|Poxvirus || ||Myxoma-fibroma virus; Yaba monkey tumor virus |
Human T-Cell Leukemia Virus
There are two important human retroviruses: human T-cell leukemia virus (HTLV), which is described here, and human immunodeficiency virus (HIV), which is described in Chapter 45.
HTLV-1 causes two distinctly different diseases: a cancer called adult T-cell leukemia/lymphoma (ATL) and a neurologic disease called HTLV-associated myelopathy (HAM) (also known as tropical spastic paraparesis or chronic progressive myelopathy). HTLV-2 also appears to cause these diseases, but the association is less clearly documented. (All information in this section refers to HTLV-1 unless otherwise stated.)
HTLV and HIV are the two medically important members of the retrovirus family. Both are enveloped viruses with reverse transcriptase in the virion and two copies of a single-stranded, positive-polarity RNA genome. However, HTLV does not kill T cells, whereas HIV does. In fact, HTLV does just the opposite; it causes malignant transformation that “immortalizes” the infected T cells and allows them to proliferate in an uncontrolled manner.
The genes in the HTLV genome whose functions have been clearly identified are the three structural genes common to all retroviruses, namely, gag, pol, and env, plus two regulatory genes, tax and rex. In general, HTLV genes and proteins are similar to those of HIV in size and function, but the genes differ in base sequence, and therefore, the proteins differ in amino acid sequence (and antigenicity). For example, p24 is the major nucleocapsid protein in both HTLV and HIV, but they differ antigenically. The virions of both HTLV and HIV contain a reverse transcriptase, integrase, and protease. The envelope proteins of HTLV are gp46 and gp21, whereas those of HIV are gp120 and gp41.
The proteins encoded by the tax and rex genes play the same functional roles as those encoded by the HIV regulatory genes, tat and rev. The Tax protein is a transcriptional activator, and the Rex protein governs the processing of viral mRNA and its export from the nucleus to the cytoplasm.
The tax gene is an oncogene and the Tax protein is required for malignant transformation of T cells. The Tax protein activates the synthesis of interleukin-2 (IL-2; which is T-cell growth factor) and of the IL-2 receptor. IL-2 promotes rapid T-cell growth and eventually malignant transformation of the T cell.
The stability of the genes of HTLV is much greater than that of HIV. As a consequence, HTLV does not show the high degree of variability of the antigenicity of the envelope proteins that occurs in HIV.
Summary of Replicative Cycle
The replication of HTLV is thought to follow a typical retroviral cycle, but specific information has been difficult to obtain because the virus grows poorly in cell culture. HTLV primarily infects CD4-positive T lymphocytes. The cellular receptor for the virus is unknown. Within the cytoplasm, reverse transcriptase synthesizes a DNA copy of the genome, which migrates to the nucleus and integrates into cell DNA. Viral mRNA is made by host cell RNA polymerase, and transcription is upregulated by Tax protein, as mentioned earlier. The Rex protein controls the synthesis of the gag/pol mRNA, the env mRNA, and their subsequent transport to the cytoplasm, where they are translated into structural viral proteins. Full-length RNA destined to become progeny genome RNA is also synthesized and transported to the cytoplasm. The virion nucleocapsid is assembled in the cytoplasm, and budding occurs at the outer cell membrane. Cleavage of precursor polypeptides into functional structural proteins is mediated by the virus-encoded protease.
Transmission & Epidemiology
HTLV is transmitted primarily by intravenous drug use, sexual contact, or breast feeding. Transplacental transmission has been rarely documented. Transmission by blood transfusion has greatly decreased in the United States with the advent of screening donated blood for antibodies to HTLV and discarding those that are positive. Transmission by processed blood products, such as immune serum globulins, has not occurred. Transmission is thought to occur primarily by the transfer of infected cells rather than free, extracellular virus. For example, whole blood, but not plasma, is a major source, and infected lymphocytes in semen are the main source of sexually transmitted virus.
HTLV infection is endemic in certain geographic areas, namely, the Caribbean region including southern Florida, eastern South America, western Africa, and southern Japan. The rate of seropositive adults is as high as 20% in some of these areas, but infection can occur anywhere because infected individuals migrate from these areas of endemic infection. At least half the people in the United States who are infected with HTLV are infected with HTLV-2, usually acquired via intravenous drug use.
HTLV causes two distinct diseases, each with a different type of pathogenesis. One disease is ATL in which HTLV infection of CD4-positive T lymphocytes induces malignant transformation. As described earlier, HTLV-encoded Tax protein enhances synthesis of IL-2 (T-cell growth factor) and IL-2 receptor, which initiates the uncontrolled growth characteristic of a cancer cell. All the malignant T cells contain the same integrated proviral DNA, indicating that the malignancy is monoclonal (i.e., it arose from a single HTLV-infected cell). HTLV remains latent within the malignant T cells (i.e., HTLV is typically not produced by the malignant cells).
The other disease is HAM, also known as tropical spastic paraparesis or chronic progressive myelopathy. HAM is a demyelinating disease of the brain and spinal cord, especially of the motor neurons in the spinal cord. HAM is caused either by an autoimmune cross-reaction in which the immune response against HTLV damages the neurons or by cytotoxic T cells that kill HTLV-infected neurons.
ATL is characterized by lymphadenopathy, hepatosplenomegaly, lytic bone lesions, and skin lesions. These features are caused by proliferating T cells infiltrating these organs. In the blood, the malignant T cells have a distinct “flower-shaped” nucleus. Hypercalcemia due to increased osteoclast activity within the bone lesions is seen. Patients with ATL often have reduced cell-mediated immunity, and opportunistic infections with fungi and viruses are common.
The clinical features of HAM include gait disturbance, weakness of the lower limbs, and low back pain. Loss of bowel and bladder control may occur. Loss of motor function is much greater than sensory loss. T cells with a “flower-shaped” nucleus can be found in the spinal fluid. Magnetic resonance imaging of the brain shows nonspecific findings. Progression of symptoms occurs slowly over a period of years. HAM occurs primarily in women of middle age. The disease resembles multiple sclerosis except that HAM does not exhibit the remissions characteristic of multiple sclerosis.
Both ATL and HAM are relatively rare diseases. The vast majority of people infected with HTLV develop asymptomatic infections, usually detected by the presence of antibody. Only a small subset of those infected develops either ATL or HAM.
Infection with HTLV is determined by detecting antibodies against the virus in the patient’s serum using the enzyme-linked immunosorbent assay (ELISA) test. The Western blot assay is used to confirm a positive ELISA result. Polymerase chain reaction (PCR) assay can detect the presence of HTLV RNA or DNA within infected cells. The laboratory tests used to screen donated blood contain only HTLV-1 antigens, but because there is cross-reactivity between HTLV-1 and HTLV-2, the presence of antibodies against both viruses is usually detected. However, some HTLV-2 antibodies are missed in these routine screening tests. Isolation of HTLV in cell culture from the patient’s specimens is not done.
ATL is diagnosed by finding malignant T cells in the lesions. The diagnosis of HAM is supported by the presence of HTLV antibody in the spinal fluid or finding HTLV nucleic acids in cells in the spinal fluid.
There is no specific antiviral treatment for HTLV infection, and no antiviral drug will cure latent infections by HTLV. ATL is treated with anticancer chemotherapy regimens. Antiviral drugs have not been effective in the treatment of HAM. Corticosteroids and danazol have produced improvement in some patients.
There is no vaccine against HTLV. Preventive measures include screening donated blood for the presence of antibodies, using condoms to prevent sexual transmission, and encouraging women with HTLV antibodies to refrain from breast feeding.
Chronic infection with HCV, like 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.)
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.
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.
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.)
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.)
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.