Adenovirus is a non-enveloped virus with a double-stranded DNA genome that commonly causes respiratory illness. It infects epithelial cells and attaches via fiber structures to the CAR receptor. Early genes induce cell cycle progression while late genes carry out DNA replication and structural protein production. Adenovirus has various mechanisms to evade host immune responses and can integrate oncogenes leading to cell transformation. Papillomavirus infects epithelial cells and its E6 and E7 oncoproteins inactivate tumor suppressors p53 and pRb to cause proliferation. Certain types are strongly associated with cancers like cervical cancer. Polyomavirus has oncoproteins that similarly inactivate tumor suppressors and can

1. ADENOVIRUS Maria Ellery M. Mendez, MD, DPASMAP, FPAMS, FPAAAMI Department of Microbiology Our Lady of Fatima University

2. PROPERTIES Virion : Non-enveloped; icosahedral, 70 – 90 nm in diameter, 252 capsomeres (12 vertices or penton bases + 240 hexon capsomeres); fiber projects from each vertex

3. PROPERTIES Composition : DNA (13%), protein (87%) Genome : Linear, double stranded DNA, 26 – 45 kbp, protein-bound to termini, infectious

4. PROPERTIES Proteins : 11 virion proteins Hexon & penton capsomeres are the major components on the surface of the virus particle Penton base with toxin-like activity Fibers – with type-specific antigens; associated with hemagglutinating activity

5. PROPERTIES Classification: Aviadenovirus (birds) and Mastadenovirus (mammals) Human adenovirus: six groups (A to F) Replication : Nucleus; only in cells of epithelial origin Attaches to cells via the fiber structures Host cell receptor: CAR (coxsackie-adenovirus receptor)  member of immunoglobulin gene superfamily

6. PROPERTIES Replication : Early Events Induce the host cell to enter the S phase of the cell cycle  create conditions conducive to viral replication Virus attachment (adsorption) Interaction of penton base with cellular integrins Virus internalization into endosomes CYTOSOL Uncoating NUCLEUS

7. PROPERTIES Replication : DNA Replication & Late Events Takes place in the nucleus Late events begin concomitantly with the onset of viral DNA synthesis Host genes continue to be transcribed in the nucleus late in the course of infection

8. PROPERTIES Virus Effects on Host Defense Mechanisms VA RNAs: prevent activation of an interferon-inducible kinase that inactivates eukaryotic initiation factor 2 E3 region proteins: inhibit cytolysis of infected cells by host responses E3 gp19-kDa protein: blocks movement of MHC class I antigen to the cell surface  protect from CTL-mediated lysis Other E3-encoded proteins: block TNF- 

9. PROPERTIES Virus Effects on Cells Oncogenes: E1A (pRB) and E1B (p53) – animals such as hamsters Cytopathic for human cell cultures, particularly primary kidney and continuous epithelial cells CPE: marked rounding, enlargement, and aggregation of affected cells into grape-like clusters without lysis of infected cells

10. PROPERTIES Immunity Induce effective and long-lasting immunity against re-infection Resistance to clinical disease directly related to presence of circulating neutralizing antibodies – persist for life Type-specific neutralizing antibodies do not always prevent re-infection Group-specific antibodies not protective and decline with time Maternal antibodies protective for infants against severe respiratory infections

11. PATHOGENESIS Infect and replicate in epithelial cells of the respiratory tract, eye, GIT, urinary bladder, and liver Usually do not spread beyond the regional LN Group C viruses persist as latent infections in adenoids and tonsils  shed in the feces for many months Most human adenoviruses replicate in intestinal epithelium after ingestion

12. EPIDEMIOLOGY Usually do not cause outbreaks of disease Most common serotypes in clinical samples: low numbered respiratory types ( 1, 2, 3, 5, 7 ) and the gastroenteritis types ( 40 and 41 ) MOT: direct contact, fecal-oral route, respiratory droplets, or contaminated fomites Infections with types 1,2,5, and 6 – chiefly during first year of life Infection with types 3 and 7 – school years Infection with types 4,8 and 19 – adulthood Types 34 and 35 – bone marrow and renal transplant recipients

13. CLINICAL FINDINGS RESPIRATORY DISEASES Cough, nasal congestion, fever, and sore throat  most common in infants and children; usually involving Group C viruses Types 3, 7, and 21: pneumonia (10-20%) in childhood Types 4 and 7 (and occ. Type 3): acute respiratory disease among military recruits; occurs in epidemic form

14. CLINICAL FINDINGS EYE INFECTIONS Pharyngoconjunctival fever Occur in outbreaks, such as at children’s summer camps (“ swimming pool conjunctivitis ”); associated with types 3 & 7 Epidemic keratoconjunctivitis More serious; types 8, 19 and 37 Adults; highly contagious MOT: fomites (e.g. sinks, hand towels) Acute conjunctivitis  keratitis

15. CLINICAL FINDINGS EYE INFECTIONS

16. CLINICAL FINDINGS GASTROINTESTINAL DISEASE Types 40 and 41 Associated with infantile gastroenteritis Account for 5-15% of viral gastroenteritis in young children Abundantly present in diarrheal stools

17. CLINICAL FINDINGS OTHER DISEASES Types 11 and 21 Acute hemorrhagic cystitis in children, especially boys; (+) virus in urine Types 1 – 7 Respiratory disease progressing to severe pneumonia in transplant patients Children with liver transplants – hepatitis Children with heart transplants – inc. risk of graft loss

18. LABORATORY DIAGNOSIS SAMPLES should be collected from affected sites early in the illness Duration of virus excretion varies among different illnesses Throat of adults with common cold: 1 – 3 days Throat, stool, and eye for pharyngoconjunctival fever: 3 – 5 days Eye for keratoconjunctivitis: 2 weeks Throat and stool of children with respiratory illnesses: 3 – 6 weeks Urine, throat and stool of immunocompromised patients: 2 – 12 months

19. LABORATORY DIAGNOSIS Virus isolation in cell culture DNA hybridization or restriction endonuclease digestion PCR Electron microscopy ELISA Latex agglutination Serology

20. TREATMENT No specific treatment for adenovirus infections

21. PAPOVAVIRUSES

22. PROPERTIES Virion : Non-enveloped; icosahedral, 55 nm diameter PAPILLOMA VIRUS

23. PROPERTIES Composition : DNA (10%), protein (90%) Genome: Double stranded DNA, circular, MW 5 million, 8 kbp

24. PROPERTIES Replication : Nucleus Highly tropic for epithelial cells of the skin and mucous membranes Viral nucleic acid found in basal stem cells Late gene expression (capsid proteins) restricted to uppermost layer of differentiated keratinocytes

25. PROPERTIES Classification : Based on: DNA sequence homology Tissue tropism – cutaneous or mucosal Association with oncogenes

26. PROPERTIES Outstanding characteristics : Stimulate cell DNA synthesis Restricted host range and tissue tropism Significant cause of human cancer, especially cervical cancer Viral oncoproteins (E6 and E7) interact with cellular tumor suppressor proteins (p53 & p105RB) Cause lytic infections in permissive cells Can immortalize (transform) non-permissive cells

27. PATHOGENESIS Infect squamous epithelial cells  induce a characteristic cytoplasmic vacuole ( koilocyte )  hallmark of infection MOT: Direct contact Sexual contact Passage through infected birth canal

28. PATHOGENESIS Squamous epithelium of skin (warts) & mucous membrane (genital, oral & conjunctival) (+) epithelial proliferation Hand, foot, throat, eyes, cervix Local multiplication Resolution (latency) Cell transformation

29. CLINICAL Wart (HPV-1 to HPV-4) Benign, self-limited  spontaneous regression Infect keratinized surfaces (hand and feet) Benign head and neck tumors (HPV 6 and 11) Oral papilloma Most common benign epithelial tumor of oral cavity Any age group; usually solitary

30. CLINICAL Laryngeal papilloma Most common benign epithelial tumor of larynx May be life-threatening due to obstruction to airway May extend down the trachea & into the bronchi

31. CLINICAL Anogenital Condyloma acuminata Squamous epithelium of external genitalia & perianal areas Rarely become malignant in healthy people Cervical dysplasia and neoplasia HPV 16 and 18

32. CLINICAL Association of HPV with Clinical Lesions HPV TYPE CLINICAL LESION SUSPECTED ONCOGENIC POTENTIAL 1, 4 Plantar warts Benign 2,4,26,27,29 Common warts Benign 3,10,28,41 Flat warts Rarely malignant 5,8 Epidermodysplasia verruciformis in patients w/ CMI deficiency 30% progress to malignancy 6,11 Anogenital condylomas; laryngeal papillomas; dysplasias and intraepithelial neoplasias Low

33. CLINICAL HPV TYPE CLINICAL LESION ONCOGENIC POTENTIAL 7 Hand warts of meat and animal handlers Benign 9,12,14,15,17,19-25, 36,46,47 Epidermodysplasia verruciformis Some progress to CA (eg, HPV-17, HPV-20) 13, 32 Oral focal epithelial hyperplasia Possible progression to CA 16,18,30,31,33 35,39,45,51,52 56 High-grade dysplasias & CA of genital mucosa; laryngeal & esophageal CA High correlation with genital & oral CA 34,40,42-44, 53-55, 58, 59, 61,62,64 66-69 Intraepithelial neoplasias (genital, other mucosal sites) Some progress to CA 75,77 Common warts in organ transplant patients 37 Keratoacanthoma Benign

34. CLINICAL COMMON WART

35. CLINICAL FLAT WARTS

36. CLINICAL PLANTAR WARTS

37. CLINICAL MULTIPLE WARTS SUBUNGUAL WART

38. CLINICAL LABIAL CONDYLOMA

39. CLINICAL INTERGLUTEAL CONDYLOMA

40. LABORATORY DIAGNOSIS Histologic examination of tissues Hyperkeratosis, koilocytosis Pap smear (+) koilocytosis DNA molecular probes & PCR – method of choice

41. PROPERTIES POLYOMA VIRUS Virion: Non-enveloped, icosahedral, 45 nm diameter Composition: DNA 10%, protein (90%) Genome: Double-stranded, circular, MW 3 million, 5 kbp

42. PROPERTIES Replication: Nucleus Classification: Humans: BK and JC viruses Simian SV40 & murine polyoma – models of tumor-causing viruses

43. PROPERTIES Outstanding characteristics: Stimulate cell DNA synthesis Viral oncoproteins (large T and small t) interact with cellular tumor suppressor proteins (large T – p53 & pRB; small t – PP2A or protein phosphatase 2A) Can cause human neurologic & renal disease May cause human cancer

44. PROPERTIES Outstanding characteristics: Establish persistent and latent infections in kidneys and lungs Large T (transformation) antigen: Binds to DNA  control early & late gene transcription and viral DNA replication Inactivates p53 & p105RB  (+) cell growth

45. PATHOGENESIS INHALATION Multiplication in RT Primary viremia KIDNEYS Transient secondary viremia IMMUNOCOMPETENT IMMUNODEFICIENT Latent indefinitely in kidney BK virus – urinary tract Hemorrhagic cystitis JC virus – CNS PML

46. CLINICAL BK and JC viruses widely distributed in human populations  (+) specific antibody in 70-80% of adult sera Infection usually occurs in childhood Both may persist in the kidneys of healthy individuals but may reactivate when immune response is impaired Reactivation: renal transplantation or during pregnancy

47. CLINICAL Primary infection Asymptomatic Pregnancy Reactivation BK virus Hemorrhagic cystitis, nephropathy, and severe renal allograft dysfunction Cause of polyomavirus-associated nephropathy in renal transplant patients

48. CLINICAL Progressive multifocal leukoencephalopathy (PML) JC virus; subacute demyelinating disease Impaired speech, vision, coordination and mentation  paralysis of arms & legs  death Normal CSF findings

49. PARVOVIRUS

50. PROPERTIES Virion: Icosahedral, 18-26 nm diameter, 32 capsomeres; non-enveloped; extremely resistant to inactivation but can be inactivated by formalin,  -propiolactone, and oxidizing agents Composition: DNA (20%), protein (80%)

51. PROPERTIES Genome: Single-stranded DNA, linear, 5.6 kbp, MW 1.5-2.0 million Classification: Parvovirinae – vertebrates Parvovirus & Erythrovirus – replicate autonomously in rapidly dividing cells Dependovirus – depend on a helper virus (adenovirus or herpesvirus) for replication Densovirinae – insects

52. PROPERTIES Replication: Nucleus Dependent on functions of dividing host cells Outstanding Characteristics: Smallest DNA virus Human pathogen, B19, has tropism for rbc progenitors

53. PROPERTIES Parvovirus B19 Only one serotype Replicates in mitotically active cells Highly tropic for human erythroid cells Cellular receptor: blood group P antigen  expressed on mature rbc, erythroid progenitors, megakaryocytes, endothelia cells, placenta, and fetal liver and heart Do not have the ability to stimulate resting cells to initiate DNA synthesis

54. PATHOGENESIS Virus in URT Local replication Viral replication in erythroid precursor cells in BM Viremia Rash & arthralgia (erythema infectiosum) Normal host (slight drop in hemoglobin) Host with chronic hemolytic anemia Aplastic crisis

55. PATHOGENESIS Principal target: immature cells in erythroid lineage Major site of virus replication: adult marrow and fetal liver Induce virus-specific IgG and IgM antibodies MOT: Respiratory route – major mode Parenteral – blood transfusion or infected blood products Vertically – mother to fetus

56. CLINICAL Erythema Infectiosum (Fifth Disease) Most common; I.P. = 1-2 weeks Children, especially elementary school age Rash on cheeks (slapped cheek appearance)  arms and legs (lace-like rash) Joint involvement prominent in adults – hands and knees – mimic rheumatoid arthritis

57. CLINICAL

58. CLINICAL Transient Aplastic Crisis Complicate hemolytic anemia – patients with sickle cell disease, thalassemias, and acquired hemolytic anemias in audlts Also occur after BM transplantation Abrupt cessation of rbc synthesis in BM Symptoms occur during viremic phase of infection

59. CLINICAL Infection in immunodeficient patients Cause chronic depression of BM and chronic anemia in immunocompromised patients Disease called pure red cell aplasia Severe anemia  dependent on blood transfusions Observed in patients with congenital immunodeficiency, malignancies, AIDS and organ transplants

60. CLINICAL Infection in pregnancy If mother seronegative, pose serious risk to fetus  hydrops fetalis (anemia + CHF) Fetal death occurs most commonly before the 20 th week of pregnancy If mother seropositive  no adverse effect on fetus No evidence of physical abnormalities

61. LABORATORY PCR – most sensitive; detected in serum, blood cells, tissue samples, and respiratory secretions Serology B19 IgM antibody – recent infection; present 2-3 months after infection B19 IgG antibody – chronic infection; persists for years

62. TREATMENT Fifth disease and transient aplastic crisis – treat symptomatically Aplastic crisis – require transfusion therapy Commercial Ig preparations – can cure or ameliorate persistent B19 infections in immunocompromised patients and those with anemia

63. Dependovirus Adeno-associated viruses Commonly infect humans but replicate only in association with a second “helper” virus, usually Adenovirus Neither cause illness or modify infection by their helper viruses Can integrate into the host chromosome  good candidate for use in gene replacement therapy