Human Papilloma Virus infections are among the most common sexually transmitted diseases and have been linked to both benign and malignant lesions of the genital epithelia (Howely, 1996). Approximately 100 genotypes have been described to date but only a small number have an important clinical impact. HPV-6 and HPV-11 are closely related and are responsible for approximately 90% anogenital wart cases (condylomata acuminata ). (Wang et al,2003)
With a small number of high risk HPV types being associated with the development of dysplasia and cervical carcinoma and with half a million diagnoses each year worldwide, invasive cervical carcinoma is the most common malignancy of women in the developing world and one which makes up ¼ of all female cancers-and so effective prophylactic vaccine(s) for the clinically relevant HPV types would be of major medical benefit. (Wang et al,2003).
A very promising vaccine approach has been in the use of virus-like particles (VLPs) -which spontaneously assemble when the papillomavirus major structural protein L1 is expressed recombinantly together with L2(the minor structural protein of the papillomavirus) or alone. It has been shown in animal models of papillomavirus infection that immunization with VLPs elicits neutralizing antibodies and will protect the animal from viral disease. The HPV VLP vaccines are currently being looked at in human clinical trials but whether humoral responses o L1 VLPs will be sufficient for long-lasting protection is not known at present. (Wang et al , 2003)
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So, a vaccine that is capable of in addition to inducing negating antibodies could bring about the eradification of infected cells through a cell-mediated immune response would be ideal. In order for the initiation of cell mediated immunity to occur it requires suitable antigen delivery. In some studies there have been reports of papillomavirus-like particle immunization of mice investiging CMI responses including CTLs to the L1 structural protein and to foreign epitopes inserted into L1. (Wang et al, 2003) So how did this fare in humans?, the VLP vaccination of humans and chimpanzees did elicit a good humoral response but the effect was only weak , infrequent and fleeting CTL responses. It is clear that the observations of mice are in this case not quite pertinent to the human vaccine advances. (Wang et al, 2003).
As I already mentioned the Papillomaviruses express only a limited range of proteins L1 and L2 as well as the early (E) expressed 5 major non structural proteins. E1 and E2 which are essential for viral DNA replication. Therefore these proteins are ideal targets in the development of vaccines and investigations into the vaccine potential of these proteins has begun in vivo. It has been shown using in vitro transient replication assays the requirement for HPV E1 and E2 in HPV DNA replication and the critical amino acid residues have been identified for each of the proteins in HPV –16 E1- substitutions in W439R and G482D were reported to inactivate the E1 DNA replicative functions.E2 – E39A substitution reduced DNA activity to background levels. (Wang et al, 2003).
Human Papilloma Virus and Cancer:
For many years the possibility that warts could be involved in cancer has been investigated and reinvestigated. It is now almost 100% sure that at least 2 types are definitely involved in the transformation of a benign wart into a cancerous tumour. The most frequently discussed wart caused carcinoma is that of the cervix. Cervical cancer is a killer, after breast cancer it is the biggest killer of women and is considered public health problem with approximately 500,000 new cases being diagnosed worldwide each year (Tonon et al, 2001).
Whilst the etiological role of specific HPV types in cervical neoplasia has been demonstrated and it is already established the precise mechanisms of transformation have to be elucidated (Tonon et al , 2001) Epidemiological studies strongly support the theory that high risk HPV types i.e. type 16, 18, 31, 33 may act as solitary cervical carcinogens (Tonon et al, 2001).
There is however a large lag time between the primary cervical high risk HPV infection and the development of lesions. Cervical cancer has greater incidence in age groups between the ages of 55 an 65, while low grade squamous intraepithelial lesions (LGSIL) are more common in the 25-35 age bracket, showing there is a 20-30 year time phrase for malignant progression (Tonon et al, 2001).
Infections by high risk HPV have been found in about 97% of all cervical carcinoma samples tested worldwide, with HPV type-16 being the most frequently detected virus type which accounts for 60% of all positive data. The biological properties of type 16 include he capability of immortalizing keratinocytes and to induce chromosomal aberrations by over riding cell cycle control mechanisms via viral oncoproteins cellular signalling interference (Tonon et al, 2001) .
The augmentation of viral E6/E7 genes from HPV 16 has been implied as a prerequisite for continued cellular growth stimulation. The E6/E7 proteins are nuclear proteins that can induce cellular DNA synthesis in growth arrested cells, morphologically transform rodent cells and immortalize primary cells. They are involved in binding of cellular regulatory proteins p53,p105,p107 and c-src (Tonon et al, 2001) .
So it is clear that there is an established link between the HPV and cancer. Further types are being studied for their cancer-causing qualities. As I mentioned there are several vaccine candidates that are being trailed in the hope we can fight back at the HPV cancer forming types.
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