Viral transformation

Cytocidal infections are often associated with changes in cell morphology, physiology and are thus important for the complete viral replication and transformation. Cytopathic Effects, often include a change in cell's morphology such as fusion with adjacent cells to form polykaryocytes as well as the synthesis of nuclear and cytoplasmic inclusion bodies. Physiological changes include the insufficient movement of ions, formation of secondary messengers, and activation of cellular cascades to continue cellular activity. Biochemically, many viruses inhibit the synthesis of host DNA, RNA, proteins directly or even interfere with protein-protein, DNA-protein, RNA-protein interactions at the subcellular level. Genotoxicity involves breaking, fragmenting, or rearranging chromosomes of the host. Lastly, biologic effects include the viruses' ability to affect the activity of antigens and immunologlobulins in the host cell.[1]

There are two types of cytocidal infections, productive and abortive. In productive infections, additional infectious viruses are produced. Abortive infections do not produce infectious viruses. One example of a productive cytocidal infection is the herpes virus.[2]

There are three types of persistent infections, latent, chronic and slow, in which the virus stays inside the host cell for prolonged periods of time. During latent infections there is minimal to no expression of infected viral genome. The genome remains within the host cell until the virus is ready for replication. Chronic infections have similar cellular effects as acute cytocidal infections but there is a limited number of progeny and viruses involved in transformation. Lastly, slow infections have a longer incubation period in which no physiological, morphological or subcellular changes may be involved.[1]

Transformation infections is limited to abortive or restrictive infections.[1] This constitutes the broadest category of infections as it can include both cytocidal and persistent infection. Viral transformation is most commonly understood as transforming infections, so the remainder of the article focuses on detailing transforming infections.

Viral transformation can impose characteristically determinable features upon a cell. Typical phenotypic changes include high saturation density, anchorage-independent growth, loss of contact inhibition, loss of orientated growth, immortalization, disruption of the cell's cytoskeleton.

Viral genes are expressed through the use of the host cell's replication machinery; therefore, many viral genes have promoters that support binding of many transcription factors found naturally in the host cells. These transcription factors along with the virus' own proteins can repress or activate genes from both the virus and the host cell's genome. Many viruses can also increase the production of the cell's regulatory proteins.[1]

Depending on the virus, a variety of genetic changes can occur in the host cell. In the case of a lytic cycle virus, the cell will only survive long enough to the replication machinery to be used to create additional viral units. In other cases, the viral DNA will persist within the host cell and replicate as the cell replicates. This viral DNA can either be incorporated into the host cell's genetic material or persist as a separate genetic vector. Either case can lead to damage of the host cell's chromosomes. It is possible that the damage can be repaired; however, the most common result is an instability in the original genetic material or suppression or alteration of the gene expression.[1]

As many as 20% of human tumors are caused by viruses.[11] Some such viruses that are commonly recognized include HPV, T-cell Leukemia virus type I, and hepatitis B.

Viral oncogenesis are most common with DNA and RNA tumor viruses, most frequently the retroviruses.[12] There are two types of oncogenic retroviruses: acute transforming viruses and non-acute transforming viruses. Acute transforming viruses induce a rapid tumor growth since they carry viral oncogenes in their DNA/RNA to induce such growth. An example of an acute transforming virus is the Rous Sarcoma Virus (RSV) that carry the v-src oncogene. v-Src is part of the c-src, which is a cellular proto-oncogene that stimulates rapid cell growth and expansion. A non-acute transforming virus on the other hand induces a slow tumor growth, since it does not carry any viral oncogenes. It induces tumor growth by transcriptionally activating the proto-oncogenes particularly the long terminal repeat (LTR) in the proto-oncogenes.[12]

Viral Oncogenesis through transformation can occur via 2 mechanisms:[1]

1. The tumor virus can introduce and express a "transforming" gene either through the integration of DNA or RNA into the host genome.
2. The tumor virus can alter expression on preexisting genes of the host.

One or both of these mechanisms can occur in the same host cell.

The Hepatitis B viral protein X is believed to cause hepatocellular carcinoma through transformation, typically of liver cells. The viral DNA is incorporated into the host cell's genome causing rapid cell replication and tumor growth.[13]

Papillomaviruses typically target epithelial cells and cause everything from warts to cervical cancer. When human papillomavirus (HPV) transforms a cell, it interferes with the function of cellular proteins while degrading other cellular proteins.[14]

The herpesviruses, Kaposi's sarcoma-associated herpesvirus and Epstein-Barr virus, are believed to cause cancer in humans, such as Kaposi's sarcoma, Burkitt's lymphoma, and nasopharyngeal carcinoma. Although genes have been identified in these viruses that cause transformation, the manner in which the virus transforms and replicates the host cell is not understood.[14]

The retroviruses include T-cell Leukemia virus type I, HIV, and Rous Sarcoma Virus (RSV). The viral gene tax is expressed when the T-cell Leukemia virus transforms a cell altering the expression of cellular growth control genes and causing the transformed cells to become cancerous. HIV works differently by not directly causing cells to become cancerous but by instead making those infected more susceptible to lymphoma and Kaposi's sarcoma. Many other retroviruses contain the three genes, gag, pol, and env, which do not directly cause transformation or tumor formation.[14]

Human immunodeficiency virus is a viral infection that targets the lymph nodes. HIV binds to the immune CD4 cell and reverse transcriptase alters the host cell genome to allow integration of the viral DNA via integrase. The virus replicates using the host cell's machinery and then leaves the cell to infect additional cells via budding.[15]

Figure 4: Type I Human Interferon

Type I interferons (IFNs) are used to treat a wide variety of medical conditions including hepatitis C, cancers, viral and inflammatory diseases. IFNs can either be extracted from a natural source, such as cultured human cells or blood leukocytes, or they can be manufactured with recombinant DNA technologies. Most of these IFN treatments have a low response rate.[16]

The use of viral transformation of the Epstein-Barr virus (EBV) has been recommended to create personalized IFNs. In this process, primary B lymphocytes are transformed with EBV. These cells can then be used to produce IFNs specific for the patient from which the B lymphocytes were extracted. This personalization decreases the likelihood of an antibody response and therefore increases the effectiveness of the treatment.[16]

When a virus transforms a cell it often causes cancer by either altering the cells' existing genome or introducing additional genetic material which causes cells to uncontrollably replicate.[11] It is rarely considered that what causes so much harm also has the capability of reversing the process and slowing the cancer growth or even leading to remission. Viruses transform host cells in order to survive and replicate; however, the immune responses of the host cell are typically compromised during transformation making transformed cells more susceptible to other viruses.[17]

The idea of using viruses to treat cancers was first introduced in 1951 when a 4-year-old boy suddenly went into a temporary remission from leukemia while he had chickenpox. This led to research in the 1990s where scientists worked to create a strain of the herpes simplex virus strong enough to infect and transform tumor cells but weak enough to leave healthy cells unharmed. Treating patients with viral transformation has the possibility of treating patients more safely and more effectively than using traditional methods, such as chemotherapy. Viruses used in the treatment of cancer gain strength and increase their effectiveness as the multiply in the body while causing only minor side effects, such as nausea, fatigue, and aches.[17]