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Viruses of Humans

Viruses of Humans. DNA VIRUSES. Parvoviridae Densivirinae Parvovirinae (Invertebrates) Bocavirus Parvovirus Dependoviruses (AAV) - Erythrovirus - Feline PV Helpers are * B19 parvovirus

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Viruses of Humans

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  1. Viruses of Humans

  2. DNA VIRUSES

  3. Parvoviridae DensivirinaeParvovirinae (Invertebrates) BocavirusParvovirusDependoviruses(AAV)-Erythrovirus - Feline PV Helpers are * B19 parvovirus - Canine PV - adenoviruses * Semian PV - Porcine PV - Herpesviruses • Mice PV - HPV - Vaccinia virus

  4. A negatively stained electron micrograph of AAV

  5. Parvoviruses are the simplest DNA viruses. • They are icosahedral in symmetry with a size of 18-26 nm. • The capsid consists of 60 capsomeres each of which is composed of two proteins; VP1 and VP2. • VP2 constitutes approximately 80% of the total protein mass of the virus.

  6. VP1 and VP2 share significant sequence identity but VP1 is longer and has a unique region external to the capsid which is accessible to antibody binding. • VP1 is necessary for stable confirmation and induction of neutralizing antibodies. • The genome of B19 is 5.6 kb in length with a molecular weight of 1.5-1.8x106 Daltons.

  7. Of all the DNA viruses, Parvoviruses seem to be among the most dependent on cellular function. • Dependoviruses (Adeno -associated viruses) commonly infect humans. • They do not appear to cause illness nor do they modify infection by their helper viruses. • AAV can become integrated at a specific site on the q-arm of chromosome 19 establishing latency with no known consequence.

  8. Parvovirus B19 was the only human pathogen until September 2005 when a new member, Bocavirus, was described. • Parvovirus B19 was Discovered by Yvonne Cossart in 1975. • In 1981, It was linked to transient aplastic crisis(TAC), and in 1983 with fifth disease. • It has been classified in the genus Erythrovirus. • Bocavirus is a cause of respiratory tract infection

  9. PapovavirusesPapillomaPolyoma Vacoulating viruses

  10. Human pathogens of the family belong to Papillomaviruses and Polyomaviruses only. • Virions are naked, icosahedral with a double stranded superhelical (circular) closed DNA genome. • They range in diameter form 40 to 45 nm for polyomaviruses and from 52 to 55 nm for papillomaviruses.

  11. Their icosahedral capsid is composed of 72 pentamers. • Each capsomere is composed of 2 (L1, L2) peptides for papillomaviruses or 3 (VP1, 2, and 3) peptides for polyomaviruses. • Their genome is 5 - 8 Kbp • They are capable of causing lytic, chronic, latent, and transforming infections depending on the host cell.

  12. Papillomaviruses • Induce warts (papillomas) in a variety of higher vertebrates, including man. • The viral nature of human warts was first indicated in 1907 by Ciuffo. • >100 different HPVs have been described on the basis of DNA sequence homology (> 50%) which fall into 16(A-P) groups that differ antigenically.

  13. Genome: Two large (E1 and E2) and several smaller (E4-E7) ORFs and a late region with two large genes (L1 and L2). • The E region codes for proteins concerned with DNA replication, transcription and transformation. • The E1 and E2 proteins are both essential for replication. • The long control region (LCR) is concerned with the control of transcription.

  14. Transformation • Binding of the E2 protein to an enhancer site on the LCR can upregulate transcription of E6 and E7. • Integration of the viral genome results in disruption of E1 and E2 with subsequent increase in expression of E6 and E7. • E7 binds Rb (P 105) and E6 binds to the tumor suppressor gene product P53 causing its rapid degradation.

  15. Polyomaviruses • They were named so because of their capacity to cause different types of tumors. • Most of them display a narrow host range and do not productively infect other species. • Two viruses are definitely associated with human disease, JC virus )JCV (and BK virus(BKV).

  16. The genome codes for large T and small t antigens. • They accumulate in the nucleus and stimulate cellular growth and are important for replication. • The early proteins are associated with immortalization and transformation. • Large T antigen binds to both Rb and P53 and prevents the induction of cell death.

  17. Adenoviruses

  18. Introduction • Rowe and colleagues (1953) • Hilleman and Werner (1954) • First given different names, these agents were called adenoviruses in 1956. • Today well over 100 members of the adenovirus group have been identified which infect a wide range of mammalian and avian hosts

  19. Introduction • Mastadenoviruses: infect mammals • Aviadenoviruses: infect birds. • 49 human adenovirus serotypes • Six groups (A-F)

  20. Structure • Naked icosahedral viruses with a diameter of 70-75 nm. • They have a characteristic Sputnik appearance. • Capsid is composed of 252 capsomeres (240 hexons and 12 pentons). Of the hexons 60 are peripentons.

  21. Structure • Each penton contains a base and a projecting fiber (10-30 nm). • The penton base and Fiber are cytotoxic and contain type-specific antigen. • The Fiber contains the VAP and acts as a hemagglutinin.

  22. Structure • At least 11 polypeptides • The outer shell is composed of seven known polypeptides of which polypeptide II is the most abundant. • The hexon protein is comprised of three tightly associated molecules of polypeptide II.

  23. Structure • Polypeptides VI, VIII, and IX are associated with the hexon protein as they likely stabilize the hexon capsomere lattice. • Five copies of polypetide III associate to form the penton base protein. • Polypeptide IV forms the trimeric fiber protein. • Peptide IIIa is penton associated

  24. Structure • Polypeptide V bridges the core to the capsid • Polypeptide VII is a major core protein around which DNA is wrapped forming a histone -like center • Polypeptide Mu • A terminal protein which is attached to the 5-end of viral DNA (two copies per virion) and serves as a primer for DNAreplication.

  25. Structure • DNA polymerase uses the terminal protein and a cytosine monophosphate as a primer. • Genome - ds DNA of 34-45 Kbp with a molecular weight of 20-25 x 106 Daltons. - A terminal protein (55kd) covalently attached to the 5-end (TP).

  26. Gene expression • Occurs in three phases termed pre-early, early, and late. • Most regulatory events in adenovirus gene expression occur at transcriptional or posttranscriptional steps. • Pre-early phase: Transcription of E1a. The E1a transcript is spliced to yield two E1a mRNAs. One of the proteins is a transcriptional activator that induces transcription of the early phase proteins.

  27. Gene expression • Early phase: Transcription of (E1b, E2, E3, E4) and (L1) followed by splicing of RNA transcripts. Progression to the late phase of gene expression with the help of protein products of at least 6 early genes then takes place. • Late phase: Coincident with DNA replication and directed by the so-called major late promoter (20 distinct viral mRNAs). Transport of mRNAs to the cytoplasm. Splicing and transport involves proteins producedin the early phase.

  28. Protein Functions • Adenoviruses employ both virally encoded and host proteins in replication. • E1A and virus-associated RNAs (VA RNAs) afford protection from α and ß interferons. • E1A and E1B activate host cell growth (S phase) and mediate transformation of cells in vitro • E1A inhibits apoptosis whereas E2 activates viral DNA replication and E3 antagonizesTNF and CTLs.

  29. Behavior In Vitro • Replicate best in cells of human origin (HEK, A549, Hep-2 and Hela). • A group reactive epitope on the hexon is used to identify all adenovirus isolates. • Adeno CPE Consist of rounding and grape-like clustering of swollen infected cells. • Group and type- specific antigens exist in hexons and type specific antigen is present in pentons.

  30. HERPESVIRIDAE

  31. Membership in the family herpesviridae is based on the architecture of the virion. • Enveloped, icosahedral capsid (100-110nm) • Average size of the enveloped virus is 200 nm • Herpes viruses are highly disseminated in nature.

  32. HSV particle

  33. Eight human herpesviruses; HSV-1, HSV-2 VZV, HCMV, EBV, HHV-6, HHV-7 and HHV-8 • Predominantly neurotropic(HSV-1, HSV-2, VZV) or predominantly lymphotropic (EBV, HHV-6, HHV-7)

  34. Virion size: 120-300 nm. • Variability is due to variable tegument thickness. • Genome: 80-150x106 (120-230 Kbp). Circularizes immediately upon release from capsid into nucleus.

  35. Biological Properties • They specify a large array of enzymes. • The synthesis of viral DNA and assembly of capsids occur in the nucleus. • The irreversible destruction of the infected cell. • They are able to remain latent in their natural hosts.

  36. Herpesviruses also vary greatly in their biological properties. - Host cell range. - Efficiency and speed of replication. - Site of latency. - Clinical manifestations of diseases they cause.

  37. Classification • Three subfamilies, alpha, beta, and gamma on the basis of biological properties. • Classification into genera is based on: - DNA sequence homology. - Similarities in genome sequence rearrangement. - Relatedness of viral proteins.

  38. Alphaherpesvirinae • HSV –1, HSV-2 and VZV. • Classified on the basis of : - A variable host range - Relative short reproductive cycle - Rapid spread in culture - Efficient destruction of infected cells - Capacity to establish latency primarily but not exclusively in sensory ganglia

  39. Betaherpesvirinae • CMV, HHV-6, HHV-7. • Classified on the basis of : - Restricted host range - Long reproductive cycle - Slow progress of infection in culture - Enlargement of infected cells (cytomegalia) - Latency in secretary glands, lymphoreticular cells, kidneys and other tissues.

  40. Gammaherpesvirinae • EBV, HHV-8 • Classified on the basis of : - Limited host range. - Replication In vitro in lymphoblastoid cells - Cause lytic infections in some types of epitheloid cells and fibroblasts - Specificity for either T or B lymphocytes - Latent virus is frequently demonstrated in lymphoid tissue

  41. Herpes Simplex Viruses • The first of the human herpesviruses to be discovered and the most intensively investigated of all viruses • Their attractions are their biologic properties • HSV-1 and HSV-2 have identical morphology and cross- reacting antigen • HSV infections of humans have been documented since ancient Greek times

  42. Viral DNA • It is composed of about 150 kbp with a molecular weight of100x106Daltons. • Two segments; short (S) and long (L), with reiterated sequences resulting in four isomeric forms. • It codes for more than 70 proteins.

  43. Gene Expression • Three gene classes - Alpha (immediate early) - Beta (early) - Gamma (late) • Alpha genes are responsible for the initiation of replication (5 genes). • Beta genes products include enzymes necessary for replication (e.g TK), and the replication proteins. They require functional alpha gene products for expression.

  44. Initially, five HSV immediate-early genes are transcribed with the assistance of an activating protein carried in the tegument. • In turn, some of these five genes then activate expression of about another dozen early genes whose protein products are needed to replicate the viral DNA. • Following DNA synthesis, about another five dozen genes are activated. These genes encode structural components.

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