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Inhibition of adenovirus cytotoxicity, replication, and E2a gene expression by adeno-associated virus

X J Jing1, V Kalman-Maltese, X Cao

  • 1Department of Biochemistry and Molecular Biology, Medical College of Ohio, 3035 Arlington Avenue, Toledo, Ohio 43614-5804, USA.

Virology
|March 7, 2002
PubMed

Insights

Adeno-associated virus (AAV) inhibits adenovirus (Ad) replication and gene expression by affecting Ad early promoters. The AAV Rep proteins play a key role in this interaction, modulating Ad gene expression differently based on E1a presence.

Area of Science:

  • Virology
  • Molecular Biology
  • Gene Regulation

Background:

  • Adeno-associated virus (AAV) and other parvoviruses are known to inhibit nonpermissive cell proliferation.
  • The precise mechanisms underlying this inhibition remain incompletely understood.
  • Adenovirus (Ad) serves as an efficient helper virus for AAV, suggesting a significant interaction between the two viruses.

Purpose of the Study:

  • To investigate the interaction between AAV and Ad, focusing on how AAV affects Ad-induced cytotoxicity and gene expression.
  • To elucidate the role of AAV replication (Rep) proteins in modulating Ad early gene expression and DNA replication.
  • To determine the direct impact of AAV Rep proteins on individual Ad early gene promoters.

Main Methods:

  • Coinfection of cells with AAV and Ad, with comparisons to UV-inactivated AAV and recombinant AAV vectors.
  • Measurement of steady-state E2a mRNA levels in coinfected cells and in a cell line inducibly expressing Rep proteins.
  • Construction of luciferase reporter plasmids for each of the five Ad early promoters and cotransfection assays with AAV rep genes in HeLa cells.

Main Results:

  • AAV, but not UV-inactivated AAV, delayed Ad-induced cytotoxicity and inhibited Ad E2a gene expression.
  • AAV significantly inhibited Ad DNA replication, an effect not observed with UV-inactivated AAV or a recombinant AAV vector.
  • AAV Rep expression, similar to AAV infection, led to decreased E2a protein and mRNA levels.
  • Rep78 protein repressed E1a, E2a, and E4 promoters but trans-activated E1b and E3 promoters.
  • In the presence of E1a, Rep78 repressed all five Ad early promoters, indicating context-dependent activity.

Conclusions:

  • AAV actively interferes with Ad gene expression and replication, impacting key early viral genes.
  • AAV Rep proteins are critical mediators of this interference, exhibiting differential regulation of Ad promoters.
  • The effect of AAV Rep proteins on Ad promoters is modulated by the presence of the Ad E1a trans-activating protein, highlighting a complex interplay between the two viruses.

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