Persistent Infections The pathogenesis of a viral infection and the response of the host are integral to understanding how cancer might arise from that background. The known tumor viruses establish long-term persistent infections in humans. Because of differences in individual genetic susceptibilities and host immune responses, levels of virus replication and tissue tropisms may vary among persons. Even though very few cells in the host may be infected at any given time, the chronicity of infection presents the long-term opportunity for a rare event to occur that allows survival of a cell with growth control mechanisms that are virus-modified.
Host Immune Responses
Viruses that establish persistent infections must avoid detection and recognition by the immune system that would eliminate the infection. Different viral evasion strategies have been identified, including restricted expression of viral genes that makes infected cells nearly invisible to the host (EBV in B cells), infection of sites relatively inaccessible to immune responses (HPV in the epidermis), mutation of viral anti gens that allows escape from antibody and T-cell recognition (human immunodeficiency virus [HIV]), modulation of host major histocompatibility complex class I molecules in infected cells (adenovirus, cytomegalovirus), inhibition of antigen processing (EBV), and infection and suppression of essential immune cells (HIV).
It is believed that host immune surveillance mechanisms usually eliminate the rare neoplastic cells that may arise in normal individuals infected with cancer viruses. However, if the host is immunosuppressed, cancer cells are more likely to proliferate and escape host immune control. Immunosuppressed organ transplant recipients and HIV-infected individuals are at increased risk of EBV-associated lymphomas and of HPV-related diseases. It is possible that variations in individual immune responses may contribute to susceptibility to virus-induced tumors in normal hosts.
Mechanisms of Action by Human Cancer Viruses
Tumor viruses mediate changes in cell behavior by means of a limited amount of genetic information. There are two general patterns by which this is accomplished: The tumor virus introduces a new “transforming gene” into the cell (direct acting), or the virus alters the expression of a preexisting cellular gene or genes (indirect-acting). In either case, the cell loses control of normal regulation of growth processes. DNA repair pathways are frequently affected, leading to genetic instability and a mutagenic phenotype.
Viruses usually do not behave as complete carcinogens. In addition to changes mediated by viral functions, other alterations are necessary to disable the multiple regulatory pathways and checkpoints in normal cells to allow a cell to become completely transformed. There is no single mode of transformation underlying viral carcinogenesis. At the molecular level, oncogenic mechanisms by human tumor viruses are very diverse.
Cellular transformation may be defined as a stable, heritable change in the growth control of cells in culture. No set of characteristics invariably distinguishes transformed cells from their normal counterparts. In practice, transformation is recognized by the cells’ acquisition of some growth property not exhibited by the parental cell type. Transformation to a malignant phenotype is recognized by tumor formation when transformed cells are injected into appropriate test animals.
Indirect-acting tumor viruses are not able to transform cells in culture.
Cell Susceptibility to Viral Infections and Transformation
At the cellular level, host cells are either permissive or non-permissive for replication of a given virus. Permissive cells support viral growth and production of progeny virus; non permissive cells do not. Especially with the DNA viruses, permissive cells are often killed by virus replication and are not transformed unless the viral replicative cycle that results in death of the host cell is blocked in some way; nonpermissive cells may be transformed. However, there are situations in which DNA virus replication does not lyse the host cell and such cells may be transformed. Nevertheless, transformation is a rare event. A characteristic property of RNA tumor viruses is that they are not lethal for the cells in which they replicate. Cells that are permissive for one virus may be non-permissive for another.
Not all cells from the natural host species are susceptible to viral replication or transformation or both. Most tumor viruses exhibit marked tissue specificity, a property that probably reflects the variable presence of surface receptors for the virus, the ability of the virus to cause disseminated versus local infections, or intracellular factors necessary for viral gene expression.
Some viruses are associated with a single tumor type, whereas others are linked to multiple tumor types. These differences reflect the tissue tropisms of the viruses.
Retention of Tumor Virus Nucleic Acid in a Host Cell
The stable genetic change from a normal to a neoplastic cell generally requires the retention of viral genes in the cell. Often, but not always, this is accomplished by the integration of certain viral genes into the host cell genome. With DNA tumor viruses, a portion of the DNA of the viral genome may become integrated into the host cell chromosome. Sometimes, episomal copies of the viral genome are maintained in tumor cells. With retroviruses, the proviral DNA copy of the viral RNA is integrated in the host cell DNA. Genome RNA copies of hepatitis C virus that are not integrated are maintained in tumor cells.
In some viral systems, virus-transformed cells may release growth factors that affect the phenotype of neigh boring uninfected cells, thereby contributing to tumor formation. It is also possible that as tumor cells collect genetic mutations during tumor growth, the need for the viral genes that drove tumor initiation may become unnecessary and viral markers will be lost from some cells.
