CHAPTER 10 Adenovirus Definitions of the virus n

CHAPTER 10 Adenovirus

Definitions of the virus: n Explant cultures of human adenoids degenerated spontaneously, isolated a new virus named adenovirus. n Adenovirus is the etiological agent of infectious canine hepatitis. 2/45

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Definitions of the virus: n The family Adenoviridae comprises (1) Mastadenovirus: infect mammalian species. (2) Aviadenovirus: infect birds. (3) Atadenovirus: infect broad host range. (4) Siadenovirus: frog, turkey, raptors, budgerigars, and tortoises. (5) Adenovirus of fish: white sturgeon adenovirus 5/45

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INTRODUCTION n Antigenic determinants associated with the inner part of hexons-structural units make up the bulk of the capsid; Hexons involved in neutralization and hemagglutination. n Genus-specific antigen: the basal surface of the penton; serotype-specific antigen: the outward-facing surface of the hexon. 8/45

INTRODUCTION n Non-enveloped, precisely hexagonal in outline, with icosahedral symmetry, 70 -90 nm in diameter. n Virions are composed of 252 capsomers: 240 hexons that occupy the faces and edges of the 20 equilateral triangular facets of the icosahedron and 12 pentons that occupy the verticles. n A penton fiber 9 -77. 5 nm in length, with a terminal knob. 9/45

INTRODUCTION n The viral genome encodes approximately 40 proteins that are transcribed after complex RNA splicing. n About one-third of the proteins are structural proteins, including a virus-encoded cysteine protease necessary for processing of some precursor proteins. n Adenoviruses agglutinate red blood cells, with hemagglutination occurring when the tips of penton fibers bind to cellular receptors and form bridges between cells. 10/45

INTRODUCTION n Adenovirus replicate in the nucleus, and their replication is facilitated by extensive modulation of the host immune response. n Viruses bind to host-cell receptors via their fiber knots and internalization is mediated by the interaction between the penton base and cellular integrins. n The genome is transcribed by cellular RNA polymerase II involving both DNA strands. 11/45

INTRODUCTION n Five early (E) transcriptional units (E 1 A, E 1 B, E 2, E 3, and E 4), two intermediate units (IX and IVa 2), and one late (L) unit from which five families of late m. RNA (L 1 to L 5) are transcribed. n Each early region is controlled by a separate promoter, whereas the late region uses the major late promoter. n The E 1 A region encodes proteins for (1) induction of cell-cycle progression to provide an environment for virus replication; (2) protection of infected cells from cytokine-induced apoptosis; (3) synthesis of viral proteins necessary for viral DNA replication. 12/45

INTRODUCTION n E 1 A and E 1 B proteins inactivate the cellular tumor suppresser gene, p 53, and thus deregulate cell-cycle progression. n Inactivation is mediated by ubiquitination of p 53 and other proteins through virus-assembled E 3 ligases, leading to proteasome-mediated degradation. n Inhibition of class I MHC antigen transport by E 3/19 K inhibits recognition of infected cells by cytotoxic T lymphocytes and NK cells. n E 3/14. 7 K blocked TNF alpha receptor and inhibited NF-κB transcriptional activity. 13/45

INTRODUCTION n Viral DNA replication, using 5’-linked 55 K protein as primer, proceeds from both ends by a strand-displacement mechanism. After DNA replication, late m. RNAs are transcribed; these are translated into structural proteins. n The primary transcript is about 29 kb; at least 18 distinct m. RNA are produced by alternative splicing. n Many adenoviruses cause severe condensation and margination of the host-cell chromatin, making nuclei appear abnormal (inclusion bodies). 14/45

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Papillomaviridae 16/45

Definitions of the virus: n Papillomaviruses are the cause of papillomas (warts). n Papillomaviruses can not yet be grown in conventional cell cultures, but their genome readily be sequenced. 17/45

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Definitions of the virus: n Papillomaviruses are ubiquitous, but individual viruses are host-species specific. n Pathogenic papillomavirus infections occur with some frequency in psittacine birds. 19/45

INTRODUCTION n The papillomaviridae family includes viruses with circular doublestranded DNA genomes. n There is little sequence homology between the genomes of papillomaviruses from different species. 20/45

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INTRODUCTION n The papillomaviridae family includes viruses with circular doublestranded DNA genomes. n Bovine papillomaviruses are genetically divergent. In dogs, papillomaviruses are the cause of epithelial plaques and papillomas of the skin and mucosal lining of the 22/45

INTRODUCTION of the oral cavity, conjunctiva, and external genitalia. n Papillomavirus virions are non- enveloped, spherical, 55 nm in diameter, with icosahedral symmetry. n The genome consists of a single molecule of circular double-stranded DNA, 6. 4 -8. 4 kb. 23/45

INTRODUCTION n The genome encodes 8 -10 proteins, two of which (L 1 and L 2) form the capsid. The E 1 -E 8 are non-structural proteins which exert regulatory and replicative functions. n Papillomaviruses are resistant to environmental insults. 24/45

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INTRODUCTION n Replication is linked to the growth and differentiation of stratified squamous epithelium of the skin and mucous membranes. n Actively dividing basal cells in the stratum germinativum are infected initially, and the virus is maintained in a proviral, latent state. 27/45

INTRODUCTION n Virus-induced hyperplasia (early virus gene products) leads to increased basal cell division and delayed maturation of cells in stratum spinosum and granulosum. n Late viral genes encoding capsid proteins in stratum spinosum and 28/53

INTRODUCTION and virions appear at this stage of cellular differentiation. n The heparan sulfate proteoglycan and syndecan-3 can serve as a human papillomavirus receptor on dendritic cells. n Transcription of early and late coding region is controlled by 29/45

INTRODUCTION separate promoters and occurs on the same DNA strand. n First, the half of the genome (the early genes) is transcribed to form m. RNAs that direct the synthesis of enzymes involved in virus replication and cell regulation. n Late m. RNAs that direct the synthesis of the structural proteins 30/45

INTRODUCTION (L 1 and L 2) involved in capsid assembly which are transcribed from the other half of the viral genome. n The regulated expression of the late (L 1 and L 2) proteins occurs only in differentiated epithelial cells or in differentiating keratinocytes. 31/45

INTRODUCTION n DNA replication begins at a single unique origin of replication (ori) and proceeds bidirectionally on the circular DNA. n An initiation complex binds to the origin and unwinds a region; nascent DNA chains are formed, one strand being synthesized 32/45

INTRODUCTION n DNA replication begins at a single unique origin of replication (ori) and proceeds bidirectionally on the circular DNA. n An initiation complex binds to the origin and unwinds a region; nascent DNA chains are formed, one strand being synthesized 33/45

INTRODUCTION continuously in the direction of unwinding, the other synthesized discontiously in the opposite direction. n It encodes a specific viral helicase. n Virions are assembled in the nucleus and are released on cell death, a consequence of cellular 34/45

INTRODUCTION obsolescence. A infected cell may produce 10000 to 100000 virions. n E 6 protein is a key component which is a transcriptional activator, and interacts with and inhibits or degrades a variety of cellular proteins, including the transcription activator, CBP/p 300 and p 53 tumor suppressor. 35/45

INTRODUCTION n It interacts with activating protein 1 in trans-Golgi processes, and it blocks the activity of paxillin, that contributes to focal adhesions between cells. n The host immune response to papillomavirus infection is directed against the virus, affording 36/45

INTRODUCTION protective immunity to subsequent infection, and against the virusinduced tumor, resulting in regression of the papilloma or fibropapilloma. n Once an animal is immune to virus or has undergone tumor regression, it is strongly resistant to reinfection, but it is virus-strain specific. 37/45

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Polyomaviridae 39/45

Definitions of the virus: n Polyomaviruses have highly restricted host ranges, and these viruses typically cause life-long, inapparent infections in their respective hosts. n The family Polyomaviridae contains 40/45

Definitions of the virus: n Polyomaviruses have highly restricted host ranges, and these viruses typically cause life-long, inapparent infections in their respective hosts. n The family Polyomaviridae contains a single genus, Polyomavirus. 41/45

Definitions of the virus: n The genome organization, virion structure, and replication strategy of polyomaviruses is generally similar to that of papillomviruses. n Virions and the genome (5 kb) are smaller than those of papillomaviruses. 42/45

Definitions of the virus: n The transcription of coding regions occurs on opposite DNA strands in polyomaviruses and on the same strand with papillomaviruses. n Polyomaviruses regulate the cell cycle and transform infected cells through their non-structural proteins. 43/45

Definitions of the virus: n Transformation of infected cells occurs by specific inactivation of the cellular p 53 tumor suppressor gene. n Reactivation of persistent, latent polyomavirus infections occurs as a consequence of immunosuppression, potentially as a result of mutations in the transcriptional control region. 44/45

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