3b

I. THE ADENOVIRUSES

  • First Isolated:

    • In 1953 in human adenoid cell culture.

    • Adenoids located in the upper respiratory tract, in lymph nodes.

  • Serotypes:

    • Approximately 100 serotypes; at least 52 infect humans.

    • All human serotypes classified in one genus within the family Adenoviridae.

    • Seven subgroups for human adenoviruses (A-G).

    • Common serotypes (1 to 7) are most prevalent.

COMMON DISORDERS

  • Adenoviruses Cause:

    • Respiratory tract infection.

    • Pharyngoconjunctivitis (pink-eye).

    • Hemorrhagic cystitis.

    • Gastroenteritis.

    • Major cause of febrile infections, particularly in young children and army recruits depending on serotypes.

    • Other possible conditions:

    • Myocarditis

    • Encephalitis

    • Aseptic meningitis

    • Hepatitis

    • Hemorrhagic cystitis

    • Some serotypes have oncogenic potential in animals but not in humans.

    • Applications in genetic therapies for DNA delivery, gene replacement therapies, vaccine development, and oncolytic therapy.

    • Many infections may be subclinical, with patients harboring the virus without symptoms.

    • Illness referred to as acute respiratory disease.

A. GENERALITIES

COMPONENTS

  • VIRION:

    • Icosahedral structure (20 sides, 12 corners).

    • Size: 70-90 nm in diameter.

    • Composition includes 252 capsomeres, 240 hexons, 12 pentons.

    • Fibers project from each vertex (penton base) causing cytopathic effects and detachment of cells.

  • COMPOSITION:

    • DNA (13%)

    • Protein (87%)

  • GENOME:

    • Double-stranded DNA, linear, 26-45 kbp, protein bound to termini, infectious.

  • PROTEINS:

    • Major outer capsid proteins containing important antigens (hexon, penton base, fiber).

  • ENVELOPE:

    • Absent (non-enveloped).

REPLICATION

  • NUCLEUS:

    • Adenoviruses replicate in the nucleus of the host.

FIBERS OF ADENOVIRUSES

  • Adenoviruses have 12 penton bases with fiber proteins aiding in attachment to host receptors, determining viral tropism.

  • Capsid Composition:

    • Mainly hexon proteins, with internal structures including protein VII bound to viral DNA, protein V linking DNA to capsid.

    • GC Content of DNA: Lowest in group A adenoviruses (types 12, 18, and 31) at 48-49%.

VIRION PROTEINS

  • Epitopes:

    • Group-specific and type-specific epitopes on hexon and fiber polypeptides.

C. GENES AND PROTEIN FUNCTIONS

  • GENE FUNCTIONS:

    • E1A:

    • Activates viral gene transcription.

    • Binds cellular growth suppressor (p105RB), promoting cell growth and transformation.

    • Inhibits activation of interferon response elements.

    • E1B:

    • Binds cellular growth suppressor (p53), promoting cell growth and transformation and inhibiting apoptosis.

    • E2:

    • Activates promoters and is associated with DNA polymerase.

    • E3:

    • Prevents TNF-α action; affects MHC I expression.

    • E4:

    • Limits viral cytopathologic effect.

    • VA RNAs:

    • Inhibits interferon response promoting pathogenesis.

PROTEINS IN CAPSID

  • Structural Proteins:

    • II: Family antigen and serotyping antigens.

    • III: Penton base protein, toxic to tissue culture cells.

    • IV: Fiber protein for attachment; contains serotyping antigens.

    • VI: Hexon-associated proteins.

    • VIII: Penton-associated proteins.

    • IX: Nonessential capsid cement.

    • IIIa: Facilitates assembly.

    • CORE V:

    • DNA-binding protein (VII and core proteins).

D. CLASSIFICATION OF ADENOVIRUSES

  • All Human Adenoviruses:

    • Classified in the Mastadenovirus genus.

  • Division:

    • Into seven groups (A-G) based on genetic, physical, and biological properties.

    • Similar GC content and tumor production potential among groups.

CLASSIFICATION SCHEMES FOR HUMAN ADENOVIRUSES

GROUP

SEROTYPES

HEMAGGLUTINATION

% G+C in DNA

ONCOGENIC POTENTIAL

A

12, 18, 31

IV

48-49

High

B

3, 7, 11, 14, 16, 21 ,34, 35, 50, 55

I

50-52

Moderate

C

1, 2, 5, 6, 57

III

57-59

Low or none

D

8-10, 13, 15, 17, 19, 20, 22-30, 32, 33, 36-39, 42-49, 51, 53, 54, 56

II

57-61

Low or none

E

4

III

57

Low or none

F

40, 41

III

57-59

Low or none

G

52

Unknown

55

Unknown

E. REPLICATION

PERMISSIVE CELLS

  • Adenoviruses replicate primarily in cells of epithelial origin.

REPLICATIVE CYCLE

  • Distinctions between early and late events, though not absolute.

    • Early genes expressed throughout the cycle; some genes expressed at intermediate times.

REPLICATION STAGES

  1. Virus Attachment, Penetration, and Uncoating

  2. Early events

  3. Replication of Viral DNA and Late Events

  4. Viral Assembly & Maturation

  • Eclipse Period:

    • Time between infection and first appearance of progeny virus.

  • PFU (Plaque-Forming Unit): Measure of infectious virus.

VIRAL ATTACHMENT, PENETRATION, UNCOATING

  • Attachment Process:

    • The virus attaches via fiber structures on receptors, mainly using CAR (coxsackie-adenovirus receptor) and occasionally MHC I as receptors.

  • Internalization:

    • The interaction promotes endocytosis. Post-uncoating, the virion enters the nucleus for replication.

ADSORPTION AND INTERNALIZATION

  • Separation of Steps:

    • Adsorption and internalization are distinct steps necessitating fiber and penton proteins interacting with cellular target proteins.

  • Endosomal Transport:

    • Majority of virus particles move quickly into the cytosol (90%) within approximately 5 minutes, mediated by acidic pH.

  • Microtubules' Role:

    • Potential involvement in transporting viruses to the nucleus.

  • Uncoating:

    • Begins in the cytoplasm and finishes in the nucleus, with viral DNA potentially releasing at the nuclear membrane.

EARLY EVENTS

  • Steps before viral DNA synthesis begins, inducing host cell to enter S phase, conducive to viral replication, and synthesizing viral products needed for replication.

REPLICATION OF VIRAL DNA AND LATE EVENTS