Human Papilloma Virus in Cervical Cancer Carcinogenesis and Its Immunology

M. Hussain
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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.
人乳头瘤病毒在宫颈癌发生中的作用及其免疫学研究
分子和流行病学研究已最终确定高危人乳头瘤病毒基因型与宫颈癌之间的因果关系。乳头瘤病毒是一种异质性很强的病毒。它们在自然界中分布广泛,但具有高度的物种特异性,不易发生突变。人乳头瘤病毒是一种包裹在衣壳中的非包膜双链DNA病毒。人乳头状瘤病毒的8公斤碱基环状基因组由早期基因(E1 ~ E7)和2个晚期基因组成。早期基因负责病毒复制、非结构性早期蛋白的转录和新病毒颗粒的组装。这两个晚期基因编码常见的衣壳蛋白。宿主的自然免疫反应指向L1蛋白的表位。当通过重组酵母或病毒载体表达时,L1蛋白折叠并自组装成空衣壳或病毒样颗粒。病毒样颗粒在抗原性和形态学上与野生病毒相似,是目前预防性疫苗的基础。不同基因型的人乳头瘤病毒感染对不同组织有趋向性。其中生殖器类型分别为6.11、16、18、30、40、50、60、70。高风险分别为16、18、31、33、38、39、45、51、52、56、58、59、68、73、82。低风险分别为6、11、40、42、43、44、54、61、70、72、81。HPV 16和18导致70%的鳞状细胞癌和80%至85%的宫颈腺癌。人乳头瘤病毒专门感染皮肤或粘膜的上皮细胞。它们通过鳞状上皮的轻微磨损或通过子宫颈转化带鳞状柱状连接的单细胞连接进入并感染基底层细胞。在一定比例的病例中,潜伏是由宿主细胞核中以小体形式存在的病毒基因组的低拷贝数维持的。HPV复杂的生命周期是在基底上腔室中完成的,在那里,karatinocyte失去了复制的能力,并最终分化。随着上皮脱落,完整的病毒粒子准备感染下一个宿主。正是由于这种复杂的相互作用,病毒不能在细胞系中培养,也不可能研制出减毒的HPV疫苗。在高级别病变和宫颈癌中,HPV基因组共价结合或整合到宿主染色体中。高危HPV的E6蛋白与抑癌基因p53结合,诱导其降解,解除对宿主细胞周期的控制。它还通过增加端粒酶的活性使细胞永生。E7基因产物与Rb基因产物相关,Rb基因是一种抑癌基因,在细胞生长的负调控中起重要作用。低危型HPV的E6和E7与p53和Rb基因结合较弱3,4。
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