Human Papillomaviruses Natural History and Virology.pptVIP

Human Papillomaviruses: Natural History and Virology Elizabeth R. Unger Ph.D., M.D. Acting Chief, Papillomavirus Section Centers for Disease Control and Prevention Papillomaviruses Non-enveloped dsDNA viruses Circular genome ~8 kb 55-nm spherical capsid coat Widely distributed in higher vertebrates Tight species specificity Tropism for squamous epithelium Associated with warts and papillomas Genome Organization Similar for all papillomaviruses Only one strand transcribed Open reading frames (ORFs) named in relation to bovine papillomavirus genes “Early” genes E1-E7 (but no E3 in HPV) “Late” genes L1 and L2, coding for major and minor capsid proteins HPV Genome: Episome Simple Genome Dependent on host cell for replication, transcription and translation Viral functions tightly linked to cellular differentiation Poly-cistronic viral transcripts Multiple promoters, multiple splice patterns Promoter usage linked to differentiation HPV URR Upstream regulatory region Also called long control region (LCR) or non-coding region (NCR) Contains transcriptional and replication regulatory elements Late genes Region of greatest genetic conservation L1 is major capsid protein Capsid is 72 pentamers of L1 Expressed L1 assembles into viral conformation, viral-like particles (VLPs) L2 is minor capsid protein Required for encapsidation of viral genome Early genes E1: Viral replication; maintains episome E2: Transcriptional regulation, co-factor for viral replication E4: Disrupts cytokeratins E5: Interacts with growth factor receptors E6: Transforming protein; p53 degradation E7: Transforming protein; Rb binding Viral Replication Replication and assembly in nucleus Infection initiated in basal epithelial cells Steady-state viral replication, some early-region transcription Presumed site of latent infection High-copy viral replication, late gene transcription and virion production limited to differentiating cells Viral Integration Not part of normal viral life-cycle Occurs r