Human Papilloma Virus in Cervical Cancer Carcinogenesis and Its Immunology

Abstract

Molecular and epidemiological studies have conclusively established causal relationship between high risk human papilloma virus genotypes and cervical cancer. Papillomavirus are a very heterogeneous group of virus. They are widely distributed in nature but are highly species specific and not prone to mutation. Human papilloma virus is a non-enveloped double stranded DNA virus enclosed in a capsid shell. The 8 kilo base circular genome of HPV is made of early (E1 to E7) and 2 Late gene. The early genes are responsible for viral replication, transcription of non structural early proteins and assembly of new viral particles. The 2 late genes encode common capsid protein. The natural host immune response is directed to epitops on the L1 protein. The L1 protein when expressed via recombinant yeast or viral vectors folds and selfassembles into empty capsids or viral like particles. Antigenically and morphologically the virus like particle resemble wild virus and form the basis of current prophylactic vaccine. There is tropism of HPV infection for different tissues by various genotypes. Of them the genital types are 6.11, 16, 18 various 30s 40s 50s 60s and 70s. High risks are 16,18,31,33,38,39,45,51,52,56,58,59,68,73 and 82. Low risks are 6, 11, 40, 42, 43, 44, 54, 61, 70, 72 and 81. HPV 16 and 18 contribute to 70% of squamous cell carcinoma and 80 to 85% of adenocarcinoma of cervix. Human papilloma virus specifically infect epithelial cells of the skin or mucosa. They enter through minor abrasion of the squamous epithelium or through single cell junction of the squamocolumnar junction of the transformation zone of cervix and infect the basal cellular layer. In a proportionate of cases latency is maintained by a low copy number of viral genome in episomal form in the host nucleus. The complex life cycle of HPV is completed in the suprabasal compartment where the karatinocytes lose their ability to replicate and are terminally differentiated. As the epithelium is shed the full virions are ready to infect the next host. It is for this complex interaction the virus cannot be cultured in cell line and development of attenuated HPV vaccine is not possible. In high grade lesions and cervical cancer, HPV genome are covalently bonded or integrated into host chromosome. The E6 protein of high risk HPV binds with cancer suppressor gene p53, induces its degradation and removes control of host cell cycle. It also immortalizes cell by increasing telomerase activity. E7 gene product associates with the product of Rb gene, a cancer suppressor gene important in the negative control of cell growth. The E6 and E7 of low-risk HPV types weakly binds with p53 and Rb gene3,4.