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Papilloma virus Computer colorized EM image. All 72 capsomeres are pentamers of the major structural protein. Copyright Dr Linda M Stannard, 1995 (used with permission) HPV comprises a group of small viruses with a double stranded DNA genome of about 8000 bp. With over 100 different types, HPV infects epithelial cells and cause lesions ranging from external warts, cervical lesions, and cancer. HPV’s are classified into low risk or high risk type: 1. Low-risk types 6 and 11 are mostly associated with genital warts, and only rarely associated with cancer 2. High risk types 16, 18, 31, 33, 35 are associated with cervical tumors (pre-cancer and malignant): HPV 16 is the most prevalent type in both low grade and cervical tumors , with HPV 16 DNA found in >99% of cervical cancer. HPV’s are contained within five evolutionary groups: Alpha, Beta, Gamma, Mu, and Nu. Alpha group contains HPV types that infect the cervix and contains over 60 members. Beta, Gamma, Mu, and Nu primarily infect skin 90% of currently classified HPV’s belong to the Alpha or Beta group HPV infects basal cells of the epithelial lining. These are actively dividing cells that will mature into squamous epithelial cells. Infection occurs in the basal cell layer and results in the establishment of viral plasmid that does not integrate into host DNA Stimulation of cell growth: is caused by HPV oncoproteins E6 and E7 which drive the cell into S-phase. Basal cells normally exit the cell cycle, but E6 and E7 viral proteins override the normal cell cycle control in infected cells Productive Infection Abortive Infection Tightly regulated gene expression Viral gene expression is de-regulated Results In cervical warts The ‘normal’ life cycle of the virus is no longer complete; no new virus produced Produces new infective viruses Inactivation of major tumor suppressor proteins abnormal cell division precursor to cancer This is normal cervical squamous epithelium. The squamous cells show maturation from basal layer to surface. http://library.med.utah.edu/WebPath/FEMHTML/FEM003.html This is cervical squamous dysplasia at high magnification extending from the center to the right. The epithelium is normal at the left. Note how the dysplastic (abnormal) cell nuclei are larger and darker, and the dysplastic cells have a disorderly arrangement. http://library.med.utah.edu/WebPath/FEMHTML/FEM008.html At high magnification, areas of neoplastic (tumor) squamous cells http://library.med.utah.edu/WebPath/FEMHTML/FEM011.html p53: 1) activates p21 Cdk inhibitor inhibits Cdk-cyclin inhibits cell cycle progression 2) Apoptosis pRb binds and inactivates transcription factor E2F CyclinE inhibits cell cycle progression inhibits Cdk2- Viral Protein E1 E2 E4 E5 E6 E7 Function Initiation of DNA replication- viral genome amplification Transcriptional regulation-viral genome amplification Role in genome amplification not fully understood Transmembrane protein found in the ER- involved in EGF-mediated receptor signalling Binds to and mediate p53 tumor suppressor protein degradation, activates telomerase Binds to and degrades pRB and mediates E2F expression of cellular proteins required for S-phase progression. Binds to and inactivates p21 L1 Formation of infectious virions L2 Allows genome packaging to begin Stage Infection of basal cells: Expression of viral proteins Viral DNA transferred to nucleus by L2 capsid 1. Genome maintenance E6/E7 E1/E2/E4/E5 2. Genome maintenance Cell Proliferation (growth) E6/E7 E1/E2/E4/E5 3. Genome Amplification E6/E7 E1/E2/E4/E5 4. Virus Assembly Virus release E6/E7 E4/L1/L2 Cervical tumors are most often caused by HPV and characterized by the appearance of abnormal squamous cells with an enlarged nucleus CIN is diagnosed by increasing severity: CIN 1- mild-moderate CIN 2- moderate-severe CIN 3- severe- CIS ( carcinoma in-situ) Approximately 20 million people are currently infected with genital human papillomavirus (HPV) in the United States (U.S.).1 Every year, about 12,000 women are diagnosed with cervical cancer, and almost 4,000 women die from this disease in the U.S.3 About 1% of sexually active men and women in the U.S. have genital warts at any given time.4 QuickStats: Prevalence of HPV* Infection† Among Sexually Active Females Aged 14--59 Years, by Age Group --- National Health and Nutrition Examination Survey, United States, 2003--2004 * Human papillomavirus. † Determined by DNA extraction from self-collected cervicovaginal swabs. § 95% confidence interval. Among sexually active females (i.e., 57% of females aged 14--19 years and 97% of those aged 20--59 years), the prevalence of HPV infection was highest for those in the youngest age groups (i.e., approximately 40% in those aged 14--19 years and 50% in those aged 20--24 years). Prevalence declined substantially after age 24 years. SOURCES: National Health and Nutrition Examination Survey, 2003--2004. Available at http://www.cdc.gov/nchs/about/major/nhanes/nhanes2003-2004/nhanes03_04.htm. Figure 43. Human papillomavirus (HPV) — Prevalence of high-risk and low-risk types among females 14 to 59 years of age reported from a national survey, 2003–2004 Note: Error bars indicate 95% confidence intervals. Both high-risk and low-risk HPV types were detected in some females. SOURCE: National Health and Nutrition Examination Survey JAMA, 2007, 297;813–819 Copyright © 2007, American Medical Association. All Rights reserved. In June 2006 the FDA licensed Gardisil, the first vaccine developed to protect against genital warts and cervical cancer. The vaccine has been widely tested in females 9-26 around the world. This prophylactic vaccine works by preventing four HPV types: HPV 16 and 18, which cause 70% of cervical cancers, and HPV 6 and 11, which cause 90% of genital warts. The vaccine has no therapeutic effect on HPV-related disease.