1. Samuel Aguazim MD Lange Chapters 37 & 38
DNA Viruses
Samuel Aguazim MD
Lange Chapters 37 & 38

2. Two types of DNA Viruses
1. Naked: Parvovirus, Papovaviruses, Adenovirus
2. Enveloped: Hepadnaviruses, Herpesviruses, Poxviruses

3. Replication
All DNA Viruses except hepatitis B duplicate their DNA by using it as a template to make more DNA Hepatitis B’s DNA polymerase has reverse transcriptase activity.

4. Virus name
DNA type
Virion associated
Polymerase
Envelope
DNA replication
Major virus
Parvo virus
ssDNA NO
NAKED
NUCLEUS
B19
Papova
dsDNA
CIRCULAR
PAPILLOMA
POLYOMA
Adeno
dsDNA linear
ADENO VIRUS
Hepadna
Partially ds DNA CIRCULAR
YES
ENVELOPED
NUCLEUS via RNA intermediate
HBV

5. Virion associated polymerase Envelope DNA replicates Major virus
Virus name
DNA type
Virion associated polymerase
Envelope
DNA replicates
Major virus
Herpes
Ds DNA linear NO
Enveloped
Nucleus/ virus assemble in nucleus
HSV
VZV
EBV
CMV
POX
Ds DNA Linear
YES
Cytoplasm
VARIOLA
VACCINIA
MOLLUSCUM
CONTAGIOSUM

8. Parvoviruses
Parvovirus B19 is a naked, single stranded DNA virus that replicates in erythrocyte precursors.
Reservior: respiratory droplet
Transmission: resp droplet, formites, vertical transmission.
Diseases
Fifth disease (erythema infectiosum, slapped cheek fever)
Chronic anemia in immunocompromised
Aplastic crises in sickle cell patients
Hydrops fetalis
Rash & arthralgias( adult predominantly)

10. Top 5 causes pediatric red rashes:
Measles a.k.a rubeola (Measles virus) Scarlet fever (S. pyogenes) Rubella a.k.a German measles or 3-day measles(Rubella virus) Roseola a.k.a Exanthem subitum, 3-day fever (HHV-6) Erythema infectiosum a.k.a 5th disease (Parvovirus B19)

11. PARVO-VIRUS
Treatment for parvovirus B19 infections is supportive. Patients who are immunodeficient can be given intravenous immune globulin (IVIG) in addition to red blood cell transfusion.

12. Papovaviruses (Papilloma virus)
Human Papillomavirus
Diseases:
HPV 1 causes Plantar Warts
HPV 2 through 4 cause Verruca vulgaris(common skin warts)
HPV 6 and 11 cause Condylomata acuminata (genital warts) and laryngeal papillomas in children. may regrow after removal but are benign.
HPV 16 and 18 are associated with intraepithelial neoplasia and Anogenital carcinoma of the uterine cervix, penis and anus. Early proteins E6 and E7 inactivate tumor suppressor functions of p53 and p110-Rb respectively.

14. Vaccine for HPV Gardacil covers HPV 6,11,16 & 18
Cervarix protects against HPV 16 and 18
DIAGNOSIS: Cutaneous- clinical ground
Genital: finding of Koilocytic cells( cells with perinuclear cytoplasmic vacuolization & nuclear enlargement) in pap smears.
Pap Smears are effective in detecting dysplastic HPV-infected cells before they transform into neoplastic cells
Treatment: Imiquimod ( induced pro- inflammatory cytokines)

16. Koilocytes

17. Papovaviruses(Polyomaviruses)
Diseases:
BK:
Reservior & transmission: respiratory
Pathogenesis: latent infection in kidney
Causes kidney disease( tubulointerstial nephritis, ureteral stenosis) and is often associated with kidney transplantation.
Diagnosis: ELISA, PCR
TREATMENT: SUPPORTIVE
VIRUS:JC RESERVIOR AND TRANSMISSION: RESPIRATORY PATHOGENESIS: Infect in oligodendrocytes= demyelination Is associated with progressive multifocal leukoencephalopathy, a slow disease of immunocompromised patients Diagnosis: ELISA, PCR TREATMENT : SUPPORTIVE

19. Adenoviruses
Naked, icosahedral ds viruses with fibers projecting from the capsid’s penton subunits.
Diseases:
Pharyngoconjunctivitis and keratoconjunctivitis: “pink eye” – conjuntivae are inflamed with a watery exudate
Acute respiratory diseases: military/vaccine serotypes 3, 4,7 & 21
Adenovirus 40 and 41: gastroenteritis
Acute hemorrhagic cystitis( boys 5-15) 11,15
Gastro enteritis ( infantile): day care( 40-41)

20. Adenovirus Fibers

22. Hepadnavirus
We will have a separate lecture for the Hepatitis Viruses

23. Herpesviruses

24. Herpesviruses Characteristics Large, linear Ds DNA
Enveloped(derived envelop from nuclear membrane), icosahedral
Intranuclear inclusion bodies
Establishes latency
Herpes simplex viruses I & II Varicella-Zoster Virus (This 3 above cause vesicular rash) Cytomegalovirus Epstein Barr Virus (EBV) Human Herpes Viruses 6 &8

25. Herpes Simplex Viruses I & II
Cause either acute or latent infections
Latent infections cannot be treated by acylovir:
reason: virus does not make thymidine kinase which is required to activate acyclovir by phosphorylation of acyclovir.

26. Herpes simplex virus HSV 1 HSV2 Latent in the lumbar or sacral ganglia
TRANS: Resp secretion and saliva
Trans: sexual transmission
Above the waist
Below the waist
Gingivostomatitis in the mouth is the most common
genital herpes
Keratoconjunctivities on the cornea, typically presenting as a branching “dendritic ulcer.”
Neonatal Infections
Esophagitis with ulcers that appear well-circumscribed and have a “volcano-like” appearance.
herpetic labialis (cold sores around the mouth)
SKIN(Recurrent vesicular cutaneous lesions(esp genitals)
focal necrotic lesion in the temporal lobe, causing inflammation and encephalitis.
Aseptic meningitis
Herpetic whitlow is a painful hand vesicle
Latent in the trigeminal ganglia
Latent in the lumbar or sacral ganglia

27. Herpes simplex geographic corneal ulcer with branching dendritic ulcer pattern.
Esophagitis with ulcers that appear well-circumscribed and have a "volcano-like" appearance.

28. Herpes simplex virus can set up a primary infection in the lips, move to the trigeminal  ganglion where it can remain latent.

29. Tzank smear

30. Gingivostomatitis looks different from a cold sore

32. Herpetic whitlow on the finger and on the wrist 

33. Genital herpes on penis area

35. NEONATAL HERPES

39. Varicella Zoster Virus
Primary Infection: Varicella or Chicken pox
Lesions start as papular and then progress to vesicular and then pustular.
Asynchronous rash
Latent in neurons
Contagious for 6 days after all lesions have dried
Live attenuated vaccine reduces the incidence of chicken pox.
Varicella Pneumonia and encephalitis(rare)
Reye syndrome (Aspirin)

41. Varicella Zoster Virus (VZV)
2. Secondary Infection:
Herpes Zoster or Shingles
Clusters of vesicular lesions, usually along a single sensory dermatome, accompanied by nerve pain
Tx: Varicella zoster immunoglobulin (VZIG) & Acyclovir
Both chicken pox and VZV are much more severe in immunocompromised patients
Prevention: live, attenuated vaccine

42. Herpes Zoster following the dermatomal pattern

43. Other manifestation
Ramsay Hunt syndrome is an otologic manifestation of herpes zoster infection that results from a reactivation of the geniculate ganglion of CN VII. The triad of symptoms include
Ipsilateral facial paralysis
Ear pain
Vesicles in the auditory canal and auricle

44. Other manifestation
Older individuals affected with herpes zoster are susceptible to post herpetic neuralgia, a condition marked by pain persisting beyond four months from initial onset.
Herpes zoster ophthalmicus is a sight-threatening condition associated with herpes zoster infections affecting the first branch of the trigeminal nerve.

45. Other manifestation
Maternal VZV infection during the first 20 weeks of pregnancy can result in 
congenital varicella syndrome. Infants present with
Cicatricial skin lesions
Limb hypoplasia
Ocular defects
CNS abnormalities

46. Cytomegalovirus (CMV)
Reservoir: Humans Transmission: Saliva, Parenteral via utero Most common cause of congenital abnormalities in neonates Pathogenesis: CMV infects epithelial cells in salivary glands-----establishes a persistent infection in epithelial cells( e.g., renal tubule cells) and macrophages and a latent infection in white blood cells----- reactivation during immunosuppression ( e.g. organ transplant) or immunocompromise ( e.g. AIDS) MHC 1- viral peptide complex is unstable in CMV- infected cells; CMV effectively thwarts cytotoxic T cell mediated killing by blocking MHC 1 expression of viral antigens on the surface of CMV-infected white blood cells

47. Cytomegalovirus (CMV)
crosses the placenta, acquired during birth, mother’s milk, direct contact, sexual contact, blood transfusions or organ transplant.
When CMV replicates, it produces cells with typical large, purple intranuclear inclusion bodies surrounded by a halo (owl’s eyes)

48. OWL’S EYE INCLUSION

49. Cytomegalovirus (CMV) Diseases
Many are asymptomatic Heterophile negative mononucleosis (immunocompetent) Retinitis and interstitial pneumonitis in immunocompromised patients Neonates: cytomegalic inclusion disease –microcephaly,seizures,deafness, hepatosplenomegaly with thrombocytopenic purpura, pneumonitis, CNS calcifications.

50. Children infected in utero with Toxoplasma, rubella, cytomegalovirus, or herpes simplex virus show remarkably similar symptoms.
Congenital CMV "blueberry muffin" baby with jaundice and thrombocytopenia purpura.

52. Periventricular calcifications of congenital CMV.

54. Dx: special tubes called shell vials PCR, The inclusion bodies are intranuclear and have an oval owl's-eye shape. 4 fold or greater rise in Ab titer Cmv antigenemia( pp65) Rx: in healthy, supportive IM ( AIDS or transplant pts) Ganciclovir and foscarnet, valganciclovir(oral), cidofovir and fomivirsen

55. Epstein Barr Virus Infects oral epithelial cells and B-lymphocytes
Diseases
Mononucleosis:
year old: called the “kissing disease”
- severe fatigue
- pharyngitis/tonsillitis similar to strep throat.
- postcervical lymphadenopathy
- hepatomegaly and spenomegaly
Burkitt’s lymphoma
-Oncogenic potential in Africa
Nasopharyngeal carcinoma – men from Southern China
Hairy Cell leukoplakia of the tongue
X-Linked Lymphoproliferative syndrome(severe, fatal)

56. Histology of lymphoid tissues in Burkitt's lymphoma from EBV infection is described as having a “starry sky” appearance from the tingible-body macrophages that have ingested apoptotic tumor cells in a backdrop of small, undifferentiated lymphocytes (“the sky”).

58. Nasopharyngeal carcinoma
EBV infection of nasopharyngeal epithelial cells may predispose to malignant transformation in certain population
( mc in Asia china)

59. Oral hairy leukoplakia of tongue in AIDS due to Epstein-Barr virus

60. Diagnosis of EBV Mononucleosis
Monospot test (Heterophile Antibody Test)
- Heterophile antibodies react with animal red blood cell antigens rather than with the virus(paul-bunnel antigen on sheep & bovine RBCs)
Tests for specific EBV antibodies to EA (early antigens) or VCA (viral capsid antigens)

61. Atypical Lymphocyte (Downey Cells): Mononucleosis

63. Human Herpes Viruses 6&8
HHV 6 : Roseola: Mcc of Infant Febrile seizures
- exanthem subitum (roseola infantum)
- high fever for 3-7 days with a maculopapular rash when the fever breaks.
HHV 8
- Kaposi sarcoma associated herpes
- Infects B cells associated with kaposi sarcoma
- seropositivity precedes sarcoma by about years
- sexually transmitted

64. Kaposi sarcoma on the nose

65. Poxviruses
Variola Virus – caused smallpox but has been extinct in the wild since 1977.
-Guarnieri bodies - large intracytoplasmic inclusion bodies caused by infection with vaccinia or variola virus.
Vaccina Virus – Is the immunogen in the vaccine which led to the sucessful eradication of smallpox.
Molluscum Contagiosum :small pink, papular, wartlike benign tumors of the skin or mucous membranes
- umbilicated lesion
- large eosinophilic cytoplasmic inclusion bodies called molluscum bodies.

67. Molluscum contagiosum showing umbilicated lesion.
molluscum Contagiosum. Notice the molluscum bodies. Credit: Ed Uthman, MD.

69. TORCHeS Toxoplasma Others: parvovirus, listeria, Enteroviruses.
Rubella
CMV
Herpes simplex, Herpes zoster (varicella), Hepatitis B,C,E, HIV
Syphilis