Introduction
It has been established that the human papillomaviruses (HPVs) cause cervical cancer. According to (medicine.jwatch.org), there are about 1400 women diagnosed with cervical cancer daily. When taken in sum, the daily diagnosis translates to a more alarming data of some 500,000 new cases and 276000 deaths yearly. The American Cancer Society (2006) announced that an estimated 10,000 cases of cervical cancer will be diagnosed in the United States and some 4000 deaths will follow (ACS, 2006). However, it has also been suggested that through the control of infection from virus types 16 and 18 will prevent cervical cancer.
Likewise, infection with anogenital warts has been found to have caused by HPV types 6 and 11 (Sinclair et al, 2005). It was further suggested that HPV causes other types of cancer to a fewer number but cervical cancer is still the most widely spread. The less common types of cancers include vulvar and vaginal cancer in women and penile cancer in men (Gonzalez et al, 2002).
The Human Papillomavirus (HPV)
Human papillomaviruses (HPVs) are circular DNA viruses that specially targeted the basal cells of the epithelial mucosa (zur Hausen and de Villiers, 1994). At present, researchers is more intrigue in identifying the potential role of HPV in the development of disease, they have identified that there are over 100 types of HPVs. There are widespread occurrences of this HPV infections and can occurring worldwide, they can be identified by the type of epithelial cells they infected and their ability to effect cells transformation. HPVs can infect the outer covering of living tissue, the mucous membrane of the oral cavity, oral part of the pharynx, and ano-genital tract and uterine cervix. HPVs ability to change cells into complex process falls into two types, the high and low risk types.
The low risk type is associated with a wound or injury but does not invade surrounding tissues such as warts, while the high risk type of infection advance the development of infection to severe and worsening of lesions. The HPV genome is consists of early (E) and late (L) genes which play a vital role in the formation of infection in the cells, sequence information of the DNA and RNA, and the creation of cancer cells. The late L1 and L2 proteins are transcribed only in the formation of infected cells; the early (E) are E1, E2, E5, E6 and E7 proteins. The E1 and E2 proteins adjust the formation of virus infection process as well as making other early viral genes functional.
E5, E6, E7 proteins are regards to be responsible to the formation of a tumor; owing to there genomic incorporation and greater growth activity properties. Boyer et al (1996) explain further that they have the ability to reduce or control tumor regulation function by interacting to and nullifying the functions of the p21, p53, and pRb proteins, as a result it defects in the process of eliminating DNA damaged, DNA repair, cell cycle control, and eventually leading to cellular immortalization.
The E5 is arranged in integrated form with the chromosome of the viral DNA, and the connected series of gene is usually loss when HPV combine (zur Hausen and de Villiers, 1994). Therefore E5 protein acts to bring its carcinogenic effects throughout the course of early stages of viral infection and this viral transformation is not necessarily needed for the maintenance of the malignant phenotype.
HPV E6 showed growth-stimulatory abilities, operating through a various mechanisms. With their association with other cell protein, E6-associated protein (E6-AP), the E6/E6-AP complex connects with p53 and targets the molecule for proteosome degradation according to Scheffner et al (1993). However, White et al (1994) stated that the effects of p53 loss are recognizable in these cells, such as the suppression of p53-mediated disintegrations, and an ineffective G1/S checkpoint in cells with DNA damage, all of which contribute to defects in cell cycle regulation and, eventually, to chromosomal instability in the infected cells.
The HPV E7 protein connects and impairs the tumor suppressor protein, pRB, by ubiquitin mediated degeneration (Boyer et al., 1996). The operative inactivity of pRB by E7 leads to overexpression of the cyclin-dependent INK4a (Khleif et al., 1996). The discovery of kinase inhibitor p16INK4a expression is conceived to be a substitute marker for p16 HPV infection.
E7 is also responsible in kinase activity by establishing complexes within cyclins A and E that thought to be responsible in driving cellular hyperproliferation (McIntyre et al., 1996).
History of HPV infection
Infection by HPV is fundamentally a sexually transmitted disease. Both men and women are included in the causes, distribution and control of infection and both can be asymptomatic carriers, transmitters and also victims of the infection by HPV (Castellsague et al, 2003). The risk factors combined with the infection of HPV are no doubt related with individual’s sexual behavior. The most important are early age at the start of the first sexual relationships, high number of sexual partners throughout life, sexual contacts with high risk individuals (Castellsague et al, 2003).
The high prevalence of HPV infections are mostly in individuals affected by Human Immunodeficiency Virus (HIV) and in women who practice prostitution. The transmission of HPV to individual is mostly by sexual contact and the most affected organ of the body that can be infected is the cervix which has the possibility of starting an abnormal proliferation of the cells.
Prevalence and Incidence of PHV infection
According to Durante et al (2003), indications of HPV infection include a high number of sex partners. Once infected with HIV, an individual is at high risk of HPV and anogenital infection. According to several studies prior to the HAART era, it has been found that almost all HIV-positive men who had intercourse with same gender were infected with multiple anal HPV infections (Palefsky et al., 1998a). On the other hand, women who are HIV-positive also have a high prevalence of cervical HPV infection (Duerr et al., 2001). It was further established that they are also highly at risk of anal HPV infection (Durante et al., 2003). HIV- positive men and women also have a high possibility with oral HPV infection (Kreimer et al., 2004).
Kreimer et al (2004) found that HIV-positive patients are at high-risk HPV infections in oral-rinse specimens at a 14% rate. There is a high risk when an individual have more than one oral sex partner within the previous one-year period. It is of note that HPV can also be acquired even without sexual contact for both men and women who were diagnosed with anal HPV infection (Palefsky et al., 2001a).
This many show that HPV can be acquired through spread from other genital sites or through fomites (Strickler et al., 2003, 2005). Fomites include tissues, forks and spoons, hairbrushes, use of infected syringes, fingers or even sex toys. However, more evidence showed that about half the HPV infections in HIV-positive women is related with sexual activity. Strickler et al (2005) suggested that other causes for almost half of those infected could be through the re-activation of previously acquired HPV.
Risk of HPV
It has been suggested that sexually active ages of 20-24 years for women and 25-29 years for men is the most important risk factor for acquiring HPV infection (Insinga et al, 2003). The increased lifetime number of sexual partners, uncircumcised men, young age at first sexual intercourse, sexual behavior of the partners, and smoking also contributes to the risk of acquiring HPV while use of oral contraceptives are additional risk factors in women (Insinga et al, 2003). Infection was also detected to some 50% of sexually active women (CDCP, 2006) where a recent 2-year study found that female university students showed that the cumulative incidence of HPV infections in among those who has sexual activity was about 40%. In addition, a 2000 US study found 74% of new HPV infections were diagnosed among individuals 15 to 24 years of age (Weinstock, 2004).
Outcome of HPV
About 70% to 90% of HPV infections among women is considered transient or varies with time (Ho L, 2003). A longitudinal study of female university students found that the median duration of new HPV infections was about 8 months. Persistence of HPV infection is indicated when the same HPV type is detected 2 or more times in several months to within a year. It was also established that factors linked with persistent HPV infection are older age, high-risk types of HPV 16 or 18, multiple types of HPV infection, as well as immune suppression (Hildesheim, 2001).
Genetic Link
To properly understand the entire genetic connection between HPV and high risk for cervical cancer, one needs to carefully inspect the linkages by which HPV influences cervical cancer. HPV is in a group of viruses known as DNA viruses, that is, viruses that attack a host and make some lasting transformation to the DNA of the infected host cells. In the cases of HPV-16 and HPV-18, the virus give rise to the oncoproteins E6 and E7, which act on each other uniquely with human cellular elements of p53 and retinoblastma.
The role of p53 in human cells is to protect DNA repair processes and to make safe of chromosomal steadiness, and the impairment of p53 leads directly to modification changes and extremely to the immortalization of human cells. The gene dominating transcription of p53 in humans is having several distinct forms at amino acid 72, comprising either a proline or arginine residue at this situation. The HPV E6 protein reduce the strength of p53, thereby producing cervical cancer.
Moreover, it has been displayed that the arginine form of p53 is more likely to be deteriorate than the proline form, because E6 can be united more efficiently to the arginine form of p53. As a result, individuals with the arginine alteration at amino acid 72 would be much more likely to develop cervical cancer. Because the precise polymorphic collection is conserved between complete cycles, the greater the attraction of E6 for p53 would account for the genetic risk factor concerned in the progression from HPV infection to completely develop in invading cervical cancer.
Progression to Invasive Cancer
Role of HPV in combining an integral whole and chromosomal unsteadiness in pathogenesis of anogenital cancer. HPV usually exists to continue to be a circular episome in low-grade lesions, but the extent of tissues with HPV DNA in the host genome expanded with increasing damage of IN and invasive cancer. When HPV incorporate, adjustment of the viral genome usually occurs with disrupted condition of E2 open reading frame, leading to loss of E2 function. E2 is essentially serves to keep under control the expression of the HPV E6 and E7 oncogenes. Since the E6 and E7 proteins provide assistance to chromosomal reliability, de-repressed expression of E6 and E7, resulting to the loss of E2 activities upon HPV integration, may contribute to increased chromosomal instability. Over time, in combination with other situations that lead to host genetic transformation, such as environmental DNA-damaging agents and epigenetic changes, progression to invasive cancer may occur.
Prevention and Early Detection of Cervical Cancer
An evaluated proposal for detection is the use of HPV DNA detection in women with cervical abnormalities where HPV DNA detection serves as a prognostic marker. Where ambiguous cytology such as ASCUS, CIN1, mild discariosis results, HPV detection is also possible. The studies concluded that the viral detection in cases of ASCUS meant the co-existence of high-grade lesions with greater sensitivity.
Therapeutical or combined prophylactic vaccines are an alternative for the prevention of HPV infections and for the treatment of established infections. Some new researches are already evaluating new molecules for the treatment of the HPV infections and associated lesions but evidence are still lacking. New inmunomodulators also indicated effectiveness in the treatment of condylomas while treatment of infections on mucous surfaces is also developed. Another study indicated the efficiency of the prophylactic vaccines Cervarix and Gardasil which were also seen as safe in prevention of cervical neoplastic lesions and vulval and genital warts.
In failure to present a clear advantage of HAART, it is also clear that individuals on HAART demand careful follow-up to put out HPV-related IN and careful follow-up after treatment. AIN presents an extraordinary problem, since there are customary no commonly used screening or treatment guidelines for this disease. More research is clearly needed in this area. Eventually, the uncommon high prevalence of high-grade AIN presents extraordinary challenges, given the demanding considerable skill of removing large sections of the anal mucosa without causing excessive morbidity.
A more concluded comprehension of the molecular pathways that is accounted for progression of high-grade IN to invasive cancer would be of immense significance in distinguishing the genetic markers that indicate an individual as being at especially high risk of progression to cancer, and therefore in need of assertive monitoring and therapy to control the development of cancer. Determination of these indication will also be an advantage to those with HPV-related neoplasia at other sites, including the cervix and oral cavity.
Current treatments and how they work on the horizon
The ideal cervical cancer vaccine would supply the most wide and maintained protection versus oncogenic HPV infection, precancerous lesions, and cervical cancer. Quadrivalent vaccine studies showed extended and striking protection against CIN 1+ and 4-month continuous infections associated to HPV types 16 and 18 (Garland, 2007) as well as, protection against genital disease related to HPV types 6 and11(Garland, 2007). A recent phase III analysis of the quadrivalent vaccine also showed partial cross-protection against persistent infections (separated by 6 months or more) and CIN or adenocarcinoma in situ (AIS) from other high-risk HPV types, including types 31 and 45 (Brown, 2007).
To this point, it is not known how these cross-protection data for persistent infection will compare with the CIN data that are available. Both vaccines were well tolerated in both female adolescents and young women.
A head-to-head trial comparing bivalent and quadrivalent vaccination is ongoing and should provide directly comparative efficacy and safety data, as well as further insight into the value and role of vaccine-induced antibody titers in cervical cancer protection.
Further research is needed to realize the full societal and economic benefit of cervical cancer vaccination. Assuming an adequate vaccination rate among adolescent girls, the United States may expect a dramatic decrease in oncogenic HPV infection and cervical cancer. In doing so, diminished costs associated with HPV infection and cervical cytology should follow. Although the duration of protection gained with vaccination remains unknown, clinical trials to assess vaccine efficacy in boys and women in their mid-to-late 20s and cross-protection beyond HPV types 16 and 18 are ongoing.
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