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Chapter 28 : Papillomavirus
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Human papillomaviruses (HPVs) primarily infect the stratified squamous epithelia of humans. Papillomavirus genotypes are classified as distinct if their genomes have less than 90% homology in the DNA sequences of the L1 open reading frame (ORF), which encodes the major capsid protein. The study of papillomavirus L1 VLPs has shown that serotypes generally correspond to genotypes. Papillomavirus genomes share the same general organization, which usually consists of eight ORFs, all located on the same strand. Three major types of cutaneous warts are recognized: deep plantar warts, common warts, and flat or plane warts. Screening strategies for anal cancer based on anal cytology have been proposed. Present therapeutic options are directed at eradicating the disease, not the infection, by destroying the lesions with physical or chemical means or by stimulating an inflammatory or immune response. A majority of these treatments have been developed empirically, but few have been thoroughly tested, and none is completely satisfactory. A section reviews the most commonly used and best-evaluated forms of treatment for HPV diseases. The current HPV VLP vaccine has not shown any therapeutic effect. Photodynamic laser therapy is an evolving and successful approach for the treatment of cutaneous warts, genital HPV diseases, and recurrent respiratory papillomatosis. The simplest and most effective office-based treatment modalities are cryotherapy and trichloroacetic acid (TCA) application. Cryotherapy, TCA application, electrosurgery, coldblade excision, and laser surgery are all appropriate for the treatment of condyloma acuminatum in the pregnant patient.
Phylogenetic tree of papillomaviruses. The tree was established on the basis of DNA sequence homology in the L1 ORF. Abbreviations: COPV, canine oral papillomavirus; CCPV, common chimpanzee papillomavirus; CRPV, cottontail rabbit papillomavirus; DPV, deer papillomavirus; EcPV, Equus caballus (horse) papillomavirus; EEPV, European elk papillomavirus; FdPV, Felis domesticus (cat) papillomavirus; FPV, Fringilla coelebs (chaffinch) papillomavirus; HaOPV, hamster oral papillomavirus; MnPV, Mastomys natalensis (rodent) papillomavirus; OvPV, ovine papillomavirus; PCPV, pygmy chimpanzee papillomavirus; PePV, Psittacus erithacus timneh (parrot) papillomavirus; PsPV, Phocoena spinipinnis (porpoise) papillomavirus; RhPV, rhesus monkey papillomavirus; ROPV, rabbit oral papillomavirus. (Tree slightly modified from reference 44 with permission of Elsevier.)
Structure of the papillomavirus virion. A cryoelectron micrograph of the HPV-1 capsid is shown (diameter, 60 nm). (Reprinted from reference 3a with permission.)
HPV genetic maps. (Bottom) linearized HPV-16 DNA map; (middle) linearized HPV-11 DNA map; (top) HPV-11 transcription map. By convention, the map origin of papillomaviruses is defined as the position homologous to the HpaI single restriction site of HPV-1. The open boxes correspond to the ORFs in the respective translation frames. The numbers above each ORF indicate the nucleotide position of the preceding stop codon (left solid vertical line) /start codon (dashed vertical line)/stop codon (right vertical line). Each HPV-11 mRNA is depicted with its cap site (solid circle), exons (thick line), introns (thin angled line), and poly(A) site (arrow). The putative corresponding proteins are indicated on the right of the mRNAs.
Organization of the HPV-16 URR. The URR begins after the stop codon of the L1 ORF and finishes at the cap site of the E6 mRNAs. The positions of some of the potential binding sites of various viral and cellular factors are indicated by the symbols placed on and below the line. E1BS, E1 binding site; E2BS, E2 binding site; ori, origin of replication; TATA, TATA box; GRE, glucocorticoid responsive element. AP-1, Oct-1, NF-1, NF-κB, Sp1, TEF-1, TFIID, and YY1 are cellular transcription factors.
Epithelial growth factor (EGF) receptor, phorbol ester, and HPV E5 protein interactions. (A) Upon exposure to a phorbol ester, phosphokinase C (PKC) gets activated and phosphorylates the EGF receptor. This allows the binding of a complex of proteins, Grb2 and Sos, that are brought in contact with the cytoplasmic membrane. The Ras protein becomes activated by Sos after exchange of GDP for GTP. This is the trigger for the actuation of a cascade of protein kinases, Raf-1, MEK, MAPK, that ultimately induces the expression of the transcription factor AP-1, which is made up of two proto-oncoproteins, Fos and Jun. The net result is a stimulation of cell proliferation and differentiation. (B) Under physiological conditions, the EGF receptor is activated by the binding of its ligand, EGF. Autophosphorylation ensues, which precipitates the sequence of events detailed in panel A. Eventually, the process stops when the EGF receptor becomes internalized by endocytosis. As the endosome becomes acidic, the EGF receptor is degraded. The acidification of the endosome is dependent on a proton pump that includes a p16 protein subunit. Papillomavirus E5 inactivates the proton pump by binding to the p16 subunit. It is believed that the undegraded EGF receptor is then recycled to the cytoplasmic membrane. The overall effect is an increase of cellular differentiation and proliferation.
Model of the biological interactions of high-risk proteins with the cell cycle and apoptosis (see text for details). Symbols: ⊕, activation; ⊖, inhibition. Thick lines with open arrowheads (➨) indicate up-regulation; the same lines with a broken end denote down-regulation. Thick gray lines represent the regulations in normal cells, whereas the thick black lines show the regulations in HPV-infected cells; thin arrows (➜) show direct interactions. Note that the symbols are not drawn proportional to the protein molecular weights and that the protein complex aggregations are not necessarily concomitant or involve the direct protein-to-protein contacts shown. DP, differentiation-regulated transcription factor polypeptide; HDAC, histone deacetylase; mdm2, murine double minute 2 protein; DLG, disk large.
Model of HPV DNA replication and encapsidation.
Drawing of the histologic features of normal skin and of a wart.
Pap smear demonstrating koilocytic atypia. In contrast to the histologic specimen, by cytology koilocytes have one or two relatively large, smooth, oval nuclei, surrounded by a very large halo of amorphous substance. (Courtesy of Clara E. Mesonero, Cape Cod Hospital, Cape Cod, MA.)
Histology of a cutaneous wart (hemalun-eosin stain; low-power view). The darkly stained layer is the stratum granulosum. Koilocytes are profuse and disrupt the stratum granulosum. The persistence of nuclei in the stratum corneum is a feature of parakeratosis. Note the thick stratum corneum. (Courtesy of Clara E. Mesonero, Cape Cod Hospital, Cape Cod, MA.)
Histology of condyloma acuminatum (hemalun-eosin stain; high-power view). The figure demonstrates many koilocytes in the stratum spinosum. Koilocytes are relatively large cells with a shrunken, irregular nucleus surrounded by a halo. (Courtesy of Clara E. Mesonero, Cape Cod Hospital, Cape Cod, MA.)
Diagrammatic representation of the nomenclature, histologic features, and distribution of associated HPV types in HPV-related cervical lesions. The dysplasia and the CIN classifications are primarily histologic classifications that are also used for cytology, whereas the Bethesda classification is designed mainly for cytology (see text for details). *, This category in the Pap classification also included atypical squamous cells of the Bethesda classification.
Immunocytochemistry of condyloma acuminatum with an antibody directed against the common papillomavirus antigen (high-power view). Several intense nuclear signals are visible. (Courtesy of Clara E. Mesonero, Cape Cod Hospital, Cape Cod, MA.)
HPV types and their disease associations a
HPV proteins and their possible functions
Tissue differentiation and HPV markers of productive infection a
Diagnostic methods for anogenital HPV infection a
Summary of cervical cancer screening guidelines a
Some common treatment modalities for cutaneous warts
Common treatment modalities for anogenital warts
Suggested approaches to the treatment of warts