The Human Papilloma virus
One of the most common virus groups in the world today affecting the skin and mucosal areas of the body, is the human papilloma virus. Over eighty different types of HPV have been identified. Different types of the human papilloma virus are known to infect different parts of the body. The most visible forms of the virus produce warts (papilloma's) on the hands, arms, legs, and other areas of the skin. Most HPV's of this type are very common, harmless, non cancerous, and easily treatable. Genital warts are known technically as condylomata acuminatum and are generally associated with two HPV types, numbers 6 and 11.
There are other forms of HPV which are also sexually transmitted, and are a serious problem. These are; HPV-16, HPV-18, HPV-31, and HPV-45. These cancer-associated types of HPV's cause growths that usually appear flat and are nearly invisible, as compared with the warts caused by HPV-6 and HPV-11. A scanning electron microscope image of one human papilloma virus. Two types of genital tract HPV in particular, HPV 16 and HPV 18, are known to cause up to 95% of cervical cancers, and new studies show that they may be linked to oral cancer as well.
A common misunderstanding results when people group viruses and bacteria into the same category of disease. Bacteria and viruses are two completely different organisms, each functioning in different and unique ways. Bacteria are one-celled organisms capable of living and reproducing independently. The major parts of a bacterium cell are; a cell wall, cytoplasm, and a nucleoid. The cell wall protects the cell and gives it shape. The cytoplasm is the fluid inside the cell where cell growth, replication, and metabolism are carried out. The cytoplasm also contains all the components for these actions such as the nucleoid, ribosomes, and plasmids. The nucleoid is the region in the cytoplasm where the strands of DNA are located. Bacteria cells reproduce through a process called binary fission. In this process, a single bacterium cell grows to twice its normal size and splits into two daughter cells. These two new daughter cells are exact copies of the original cell. When bacteria infect a body, they do so by multiplying inside the organism and producing toxins that infect surrounding cells or tissues. But very few bacteria are harmful. 99% of the bacteria found in the body are helpful, and most are actually necessary for life. Harmful disease-causing bacteria can be eliminated or killed with antibiotics.
Viruses on the other hand, exist and function in an entirely different manner than bacteria. They are not an independent organism. When a virus is alone it is not metabolically active like bacteria; it needs a host cell to function, and in which to reproduce. A virus is composed of only a protein capsule that encloses its DNA or RNA. When a virus comes in contact with a cell, it is capable of inserting its genetic material into that host cell. Once the virus has invaded a host cell, it can go into two phases: lysogenic or lytic. During the lysogenic phase, the virus remains dormant in the cell and does not affect the host cell. The host cell continues to function normally, even though the virus has invaded it. During the lytic phase, the virus takes over the host cell and uses it to reproduce more viruses.
Once in the lytic phase, the virus's genetic material takes over the cell functions and controls the reproduction process. The viral genetic material orders the host cell to produce proteins and copies of viral DNA or RNA. The viral proteins then assemble into protein coats, and the viral DNA or RNA is packaged inside the coats. This produces many more viruses inside the host cell. When this reproductive process is complete, the host cell dies and the newly produced viruses are released to infect other cells. Unlike bacteria, a virus cannot be destroyed with antibiotics. Although there is currently no medical cure to eliminate a papilloma virus infection, the squamous intraepithelial lesions (SILs) and warts these viruses cause can be treated. Methods used to treat SILs include cold cautery (freezing that destroys tissue), laser treatment (surgery with a high-intensity light), LEEP (loop electrosurgical excision procedure, the removal of tissue using a hot wire loop), as well as conventional surgery. Similar treatments may be used for external genital warts. In addition, two powerful chemicals (podophyllin and trichloroacetic acid) are capable of destroying external genital warts when applied directly to them. Imiquimod cream has also been recently approved by the Food and Drug Administration (FDA) as an effective drug treatment. Imiquimod works by stimulating the immune system to fight the virus. Once infected with a virus, it may become part of the organism indefinitely. While there may not be outward signs of its presence, it goes through periods of dormancy undetected. A common example of this is the herpes simplex virus that causes the cold sores on your lip.
The human papilloma virus is a double-stranded DNA virus that infects the epithelial cells of skin and mucosa. The epithelial surfaces include all areas covered by skin and/or mucosa such as the mouth, throat, tongue, tonsils, vagina, penis, and anus. Transmission of the virus occurs when these areas come into contact with a virus, allowing it to transfer between epithelial cells.
It is not known why certain HPV types target skin on the hands or feet, while others attack the cells lining the mouth, and still others the genitalia of both males and females. The most dangerous HPV's, 16 and 18, are transmitted through sexual contact. These HPV's can produce two kinds of abnormal tissues, condyloma tissue and dysplasia tissue. Condyloma tissues are the wart-like growths. These warts are usually painless, but can cause some irritation, itching, or burning. This tissue appears like a small, cauliflower-type growth on the skin. It can be treated whenever it flares up, and is non malignant. Dysplastic tissue is the presence of abnormal cells on the surface of the skin. Dysplasia is not cancer, but it is a precursor tissue change prior to malignancy. In one example of a cells' transition from normal to cancerous, dysplasia can be detected on the female cervix through a Pap smear test, or visually can be seen by using a magnifying glass called a colposcope.
While not much is known about how HPV's function, scientists know much about the biology of the virus. The virus has eight genes that are categorized as being either early or late, according to the time of their expression in the HPV life cycle. The early genes E1 and E2 are involved in viral genome replication and transcription control. Transcription is the process of constructing a messenger RNA molecule that holds a copy of the genetic information from the DNA. The role of the E4 gene is still not known, but it is thought to promote the productive phase of the papilloma virus life cycle. The E5 gene enhances the activity of epidermal growth factor. E6 and E7 interfere with the host cell's control of transcription and the cell cycle. The late genes L1 and L2 encode viral capsid proteins used in the construction of new viruses.
The most dangerous aspect of the human papilloma virus is its potential to cause cancer. A highly studied topic is HPV's ability to cause cervical cancer. Normal cell division is regulated by two genes, Rb and p53. Rb segregates the transcription factors necessary for progression through the cell cycle. This means that the Rb prevents the cell from dividing until it has isolated enough proteins for cell division. The important protein which Rb segregates is E2F. This makes Rb a tumor suppressor gene/protein. It does not allow the cell cycle to continue until it has accumulated enough proteins, especially the E2F protein. When a cell is infected with HPV, the E7 gene binds to Rb so that the Rb releases E2F and the other proteins. This is a signal for the cell cycle to progress. As long as the E7 stays attached to Rb, the cell cycle will continue to happen, thus causing a cycle of uncontrolled cell reproduction, which is one of the definitions of a malignant cell.
The other gene HPV attacks is p53. Within a cell, p53 functions in response to DNA damage. When cell DNA is damaged, p53 stops cell division and directs the genes involved in DNA repair to correct the damage. If the DNA cannot be repaired, p53 then induces programmed cell death (apoptosis), ensuring that a damaged cell dies and does not reproduce. In cancerous cells, p53 is often found to be damaged or nonfunctional. This allows cells with damaged, or altered DNA to continue living instead of being destroyed. Viral E6 protein can bind to p53, and make it inactive. This allows the virus to take over the cell and reproduce itself, since the virally inhibited p53 cannot stop it, or begin the process of cell death. The repeated replication of cells with incorrect DNA information is the beginning of malignant tumor formation. Along with blocking the cell's p53, the viral E6 protein activates telomerase, an enzyme that synthesizes the telomere repeat sequences. Activating this enzyme maintains a repeated cell cycle that continues to produce viral cells. This leads to malignancy as the mutant cells continue to reproduce out of control.
The two most harmful human papilloma viruses are HPV 16 and HPV 18. Both of these are genital viruses which are spread through sexual contact. These types of the human papilloma virus have E6 and E7 proteins with very strong binding capabilities. This allows HPV 16 and HPV 18 to reproduce quickly and in great numbers, leading to uncontrolled reproduction of viral cells, and eventually cancer. It is well established that HPV 16 and HPV 18 are causative factors in cervical cancer, and now these two HPV's are also being linked to oral cancer. A study done by Dr. No-Hee Park showed that the mouth was, at the cellular level, structurally very similar to the vagina and cervix. Both organs have the same type of epithelial cells that are the target of HPV 16 and HPV 18. The majority of oral cancers are cancers of epithelial cells, primarily squamous cell carcinomas, not unlike the cancers that affect the cervix. This first step in understanding the similarities of these tissues and the disease that affects them, led to research that was able to link oral cancers to HPV. Dr. Park's study also showed that smoking and drinking alcohol help promote HPV invasion. Alcoholic beverages contain ethanol alcohol, and ethanol is known to inhibit the production of the p53 protein. The carcinogens in tobacco have been shown to damage cell DNA, the precursor event to malignancy. Combine tobacco and alcohol with HPV, and the epithelial cells in the mouth, and you may have the formula for the development of an oral cancer. A recent study conducted by the Johns Hopkins Oncology Center furthered the premise that HPV is linked with certain types of oral cancer. Dr. Maura Gillison was the head of a study which tested 253 patients diagnosed with head and neck cancers. In 25% of these cases, the tissue taken from tumors was HPV positive. HPV 16 was present in 90% of the positive HPV tissues.This information helps to confirm that there is a strong link between HPV and oral cancer. Other important information came from these studies.
Dr. Gillison wrote;
An overview of HPV and oral cancer By Dr. Robert Haddad from the American Society of Clinical Oncology (ASCO) meeting in 2007
We found that HPV-positive HNSCC [head and neck squamous cell carcinomas] had significantly improved disease-specific survival when compared with patients with HPV-negative tumors, even after adjustment for age, lymph node status and heavy alcohol consumption.
Further research is being conducted into the relationship of HPV with many other cancer types, and with oral cancers in particular. At least 25% of those diagnosed with oral cancer are non-smokers. The other 75% of those diagnosed have used tobacco in some form during their lifetimes. As smoking is the number one causative agent in oral cancers, the research into the relationship of HPV and oral malignancies gives us clues as to the origin of cancer in those 25% of diagnosed individuals who did not smoke. However, given the decline of tobacco use over the last ten years in the US, and the stable (or increasing in 2007) rate of incidence of oral cancers, it is likely that the 75% -25% is no longer an accurate representation of the situation. In the foundation's opinion, HPV is playing a greater role in the incidence rates of the disease, and the now decades old Mashberg paper which presented these percentages is outdated. However at this time new overview studies of the causes of oral cancer are not available.Risk factors for head and neck cancer with a focus on HPV from the Journal of Dental Research, 2007
Changing patterns of tonsillar squamous cell carcinoma in the United States National Cancer Institute 1999
Tongue and Tonsil Carcinoma (Increasing Trends in the U.S. Population Ages 20–44 Years) The American Cancer Society 2006
HPV Communication: Review of Existing Research and Recommendations for Patient Education From the Journal Cancer 2004