PKA/PrKX activity is a modulator of AAV/adenovirus interaction.
Interference between viruses occurs when infection by one virus results in the inhibition of replication of another virus. Adeno-associated virus (AAV2) is a human parvovirus with the unique characteristics of a dependence upon a helper virus for a productive infection and the ability to interfere with the replication of the helper virus. Previously, we demonstrated that AAV2 Rep78 and Rep52 interact and inhibit cAMP-dependent protein kinase A (PKA) and its novel homolog PrKX. We hypothesized that modulation of PKA activity by AAV2 may be responsible for inhibition of helper virus replication. In this study we demonstrate that adenovirus replication is sensitive to PKA activity and that AAV2 Rep78/Rep52 proteins contain an inhibitory domain similar to that of the heat-stable PKA inhibitor. This domain, while not directly necessary for AAV2 replication and packaging, is necessary to preserve AAV2 replication fitness during an Ad co-infection. Furthermore, a mutant AAV2 virus lacking this region fails to inhibit adenovirus replication. Thus, inhibition of PKA activity by AAV2 constitutes a novel form of viral interference.
Di Pasquale
Giovanni
G
Gene Therapy and Therapeutics Branch, NIDCR, NIH 10/1N113, 10 Center Drive MSC 1190, Bethesda, MD 20892-1190, USA.
Chiorini
John A
JA
D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D017931:DNA Primers; D004268:DNA-Binding Proteins / Q000378:metabolism; D000229:Dependovirus / Q000502:physiology*; D006367:HeLa Cells; D006801:Humans; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D017386:Sequence Homology, Amino Acid; D014764:Viral Proteins / Q000378:metabolism; D014779:Virus Replication
D017931:DNA Primers; D004268:DNA-Binding Proteins; D014764:Viral Proteins; C068734:rep proteins, Adeno-associated virus 2; D017868:Cyclic AMP-Dependent Protein Kinases