Virology Ch. 23 Adenoviruses: Structure, Infection, and Therapeutic Applications

  • Large DNA Viruses of Eukaryotes

    • Genome sizes range from 35 kb to over 1000 kb

    • Diverse group of viruses

    • Adenoviruses:

    • Smallest with linear DNA genome

    • Early genes transcribe immediately upon entry, inducing cellular machinery for DNA replication

    • Herpesviruses, poxviruses, and baculoviruses:

    • Intermediate genome sizes

    • Uniquely, poxviruses replicate in the cytoplasm

    • Viruses of algae:

    • Among the largest known viruses (up to 500 kb)

    • Mimivirus:

    • Considered a giant among viruses (1.2 Mb)

  • Adenoviruses Characteristics:

    • Virion Structure:
    • Naked icosahedral capsid (T=25) with 20 triangular faces
    • Knobbed fibers that protrude from each of 12 vertices
    • Comprises 11 proteins, linear double-stranded DNA with short inverted terminal repeat sequences
    • Both 5' ends are covalently bound to a virus-coded terminal protein

  • Host Interactions:

    • Family: Adenoviridae (from Greek adenos, meaning gland, where first isolated)
    • Fifty human serotypes in six subgroups (A through F)
    • Also found in cattle, mice, birds, etc.
    • Responsible for respiratory and enteric infections in humans, including pneumonia and gastrointestinal infections
    • Adenoviruses can be oncogenic but do not cause cancer in humans

  • Infection Mechanism:

    • Cellular receptor used is the Coxsackie and Adenovirus receptor (CAR), a member of the immunoglobulin family
    • Adsorption allows Ad2 and Ad5 to use integrin proteins as secondary receptors
    • Entry into cells occurs via endocytosis

  • Gene Expression Control:

    • Gene expression is regulated at the transcription level, divided into Early, Intermediate, and Late classes
    • VA genes transcribed by cellular RNA pol III inhibit RNA-dependent protein kinase (PKR)
    • E1A Proteins:
    • Key activators in adenovirus growth cycle
    • Act as transcriptional activators for viral and cellular genes, contributing to oncogenic potential

  • Replication Process:

    • E1A proteins bind to retinoblastoma protein (Rb), activating E2F (a transcription factor)
    • Histone deacetylases bound to Rb induce transcriptional repression of E2F-regulated genes
    • Phosphorylation of Rb by cyclin-dependent kinases during G1 phase prevents its binding to E2F

  • Cell Death Induction:

    • E1A indirectly induces apoptosis through activation of cellular p53 protein
    • p53 regulation occurs via ubiquitin-mediated degradation
    • Key Interactions:
    • E1A blocks p53 activation, while E1B proteins suppress E1A-induced apoptosis and degrade critical proteins
    • E1B protein 19K homologue of Bcl-2 prevents apoptosis by preventing the caspase cascade
    • E1B protein 55K binds to p53 to block apoptosis

  • Adenovirus-induced Cell Killing:

    • E3 “death protein” found in Golgi, ER, and nuclear membranes; exact killing mechanism is unknown
    • E4orf4 protein induces cell death independent of p53
    • Human cell infections lead to cell death with no transformation, but rodent cells can be transformed by human adenoviruses in culture

  • Therapeutic Applications:

    • Adenoviruses can be manipulated to express genes
    • Used as vectors for vaccines and gene therapy for human deficiencies
    • Commonly used strains are those with deleted E1A and E1B genes
    • New cancer therapies, such as viral strain ONYX-015, a mutant that does not express E1B, allowing replication in cancer cells where p53 is often inactivated.