VIRUSES
Biological carcinogens – why we should care?

Viruses are intracellular parasites that replicate using the cell’s internal environment and organelles. During a viral infection of a cell, a viral particle (occasionally only a portion; always the viral genetic information) invades the cell, exposes the viral genetic information, and initiates the expression of this information. Various viruses have various replication requirements, and their replication mechanisms are also distinct (for instance, DNA and RNA viruses exhibit the most striking differences). Regardless, viral genetic information and viral proteins are external molecules that can interact with both cellular proteins and the cellular genome. This interaction can have numerous effects, including the initiation of the malignant transformation process.

Significant oncogenic viruses:

Human papillomavirus (HPV)

This is a DNA virus that occurs in over 180 identified subtypes. It has a high affinity for epidermis, mucous membrane, and keratinocyte epithelia. In addition to causing warts, the papillomavirus is linked to several benign hyperplasias and tumors, as well as some highly malignant tumors, such as cervical cancer. It is transmitted through physical contact between infected body regions, most commonly during sexual activity, with the integrity of the surface significantly facilitating transmission. Subtypes 6 and 11 are primarily associated with mild dysplasia (they are identified in up to 90% of cases of genital warts); subtypes 16, 18, 31, 33, 35, and 51 are associated with heavier malignant neoplasias (they are identified in up to 85% of cases of cervical cancer). Probably associated with the integration of the viral genome into the cell genome is the transformational activity. In benign hyperplasias, viral genetic information is located on episomes outside of the cell genome, whereas in malignancies, the viral genome is incorporated into the cell genome. This integration is random, but in the case of multicellular carcinoma, the virus is integrated in all cells at the same location, indicating that this integration occurred prior to the clonal expansion of the original infected – and subsequently transformed – cell.

The Ebstein-Barr virus (EBV)

The Ebstein-Barr virus (EBV) is a herpesvirus. It is recognized as the agent responsible for infectious mononucleosis and a virus linked to the development of a number of cancers. The majority of these are Burkitt’s lymphoma, nasopharyngeal carcinoma, numerous Hodgkin’s and non-Hodgkin’s tumors, and possibly some undifferentiated stomach cancers. The EB virus has the highest affinity for oropharyngeal epithelial cells and B lymphocytes (but not for T and natural killer cells). The virus enters B lymphocytes via the surface molecule CD21; it replicates and causes latent infection, where it persists in the form of episomes in B lymphocytes (according to estimates, up to 90 percent of the Czech population has latent infection). Unlike HPV transformation, EB virus transformation is complex and not directly linked to the inactivation of tumor-suppressor genes. A number of viral proteins interact with cellular molecules, resulting in the immortalization and transformation of infected cells.

Hepatitis B and C viruses (HBV, HCV)

Although they are taxonomically distinct (HBV is DNA virus; while HCV is RNA virus), they will be described together because they both cause a certain form of viral hepatitis and are believed to be associated with liver malignancy. Infection with HBV is much more strongly suspected to have a transformative effect than infection with HCV. The function of HBV in the process of malignant transformation is not completely understood; however, the virus’s genome can be isolated from tumor cells in nearly all cases of HBV-associated liver cancer. Similar to HPV infections, the genome of the virus is incorporated into the cell’s genome (in the same location, which corresponds to the clonal expansion of the transformed cell). Let us also discuss the effect of the viral Hbx protein, which influences the transcription of specific cellular genes (primarily genes whose products promote cell proliferation) and can interact with the p53 protein. However, HBV transformation is likely indirect and multifactorial overall. In the case of HCV, the transformation effect is only substantiated by epidemiological studies; the genome of transformed cells has not been isolated. Generally, the proliferative-regenerative activity of liver cells is elevated in viral hepatitis type C, which is frequently associated with the potential transformative effect of HCV infection. In the case of HBV, it should be noted that there is a reliable vaccine that protects against HBV infection and, consequently, liver cancer induced by this infection.

Kaposi's sarcoma virus (KSHV)

Human herpesvirus 8 This herpesvirus is linked to the development of Kaposi’s sarcoma, particularly in individuals with immunosuppressive therapy or immunodeficiency (as is the case with AIDS). However, Kaposi’s sarcoma can also be endemic (in Africa) or sporadic. Despite the fact that the KSHV genome can be isolated from nearly all tumor cells, there are still numerous unanswered questions concerning transformation mechanisms. Almost certainly, KSHV infection alone is insufficient to transform a cell; additional cofactors are necessary. This cofactor may be, for instance, immunosuppression in HIV infection or HIV infection itself (then, of course, the question arises as to what this cofactor is in HIV-negative patients with Kaposi’s sarcoma). Possible KSHV transformation mechanisms include a cyclin D homologue of viral origin and multiple p53 inactivators.

Herpes simplex virus type II (HSV-2)

This virus is believed to be closely linked to cervical cancer, where it appears to function as an HPV cofactor.

Human immunodeficiency virus (HIV)

Human immunodeficiency virus (HIV) – is a retrovirus recognized as the human agent responsible for AIDS. This syndrome is also associated with the development of certain malignancies, including Kaposi’s sarcoma, certain non-Hodgkin’s B-lymphomas, and cervix and rectum cancers. However, it appears that HIV does not have a direct oncogenic potential, and that other viruses (KSHV, EBV, and HPV) are responsible for the transformation, while HIV merely „makes the job easier“ by inducing immunodeficiency.