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The Human Papilloma Virus and Its Life CyclePresentation by: Sulav Acharya
Introduction Papilloma Viruses warts ( papillomas ) in variety of higher vertibrates. Human pappilomaviruses cervical cancer and other epithelial tumours. Cause sexually transmitted disease. In cervical cancer ,HPV DNA more than 90 percent cases. More than 120 types of HPV have been identified.
Virion Structure Small, non enveloped, icosahedral DNA viruses replicate in nucleus of squamous epithelial cells. 52-55 nm diameter, DNA about 8000 bp, Spherical protein coat or capsid composed of 72 capsomers.
Long control region Early promoter Late promoter E1 E2 E4 E5 E6 E7
L1 Structural proteins L2 P97 = Early promoter P670= Late promoter AE = Early poly (A) signal AL = Late poly (A) signal
Figure 1. The genome organization of HPV16
HPV Gene Function E1 Viral genome replication with helicase/ ATPase activity. E2- is a Transcription factor transactivation and transrepression. E6 and E7 Reactivation of cellular replication mechanism,proliferation,immortalization,inhibiti on of apoptosis, maintenance of viral genome. E4 asscociated with cytokeratins to destabalize the cytokeratin network and aid in viral release at the epithelial cell layer surface, though primary function still unknown. E5 possibly involved in proliferation and /or inhibition of apoptosis. L1 Major Capsid Protein L2 Minor Capsid Protein
HPV Life CycleEating, drinking and est.
HPVs Damaged areas of the epithelium
Heparan sulfate proteoglycan recepter
Infect the basal cell
Infection and Uncoating HPV invade damaged areas of the epithelium an infect basal cells. Controversy cell surface receptor so that Virus gets attached to cell. Heparin Sulphate and endocytosis of clathrin coated vesicles attachment. Disruption of intracapsomeric disulphide bonds so virus enters the DNA
Genome maintenance Low copy number episome basal cells of the epithelium. E1 and E2 proteins maintain the viral DNA as an episome and facilate correct segregation of genomes during cell division. Finally suggested that expression of E1 and E2 is sufficient for basal maintenance of viral episomes.
Proliferative Phase In uninfected epithelium, basal cells exit cell cycle after migrating to suprabasal cell layers and undergo process of terminal differentiation. In Viral infection E7 and E6 expressed, therefore restraint on cell cycle progression is abolished and normal terminal differentiation is retarded. E7 associates with pocket protein family such as pRb. pRb- negative regualtor of cell cycle prevents S-phase entry by association
Cont.. E7 binding to pRb displaces E2F leads to the protein necessary for DNA replication. E7 in cell proliferation histone deacetylases, components of Ap-1 and the cyclin dependent kinase inhibitor p21 and p27. The Viral E6 protein associates with p53, and inactivation of p53 mediated growth suppression and apoptosis takes place. E6 predisposing factor for cervical
Papilloma virus amplify to produce infectious virions. Occours mid or upper epithelial layers and increase the activity of late promoter. Late promoter resides in E7 ORF increase expression of proteins involved in Viral DNA replication.
Encode 2 structural proteins in upper layer of infected tissue. L1 Major coat protein express after L2 which assemble the infectious particle in upper layer. L2 Minor coat protein that express E4.