Adenovirus type 5 exerts genome-wide control over cellular programs governing proliferation, quiescence, and survival.
BACKGROUND
Human adenoviruses, such as serotype 5 (Ad5), encode several proteins that can perturb cellular mechanisms that regulate cell cycle progression and apoptosis, as well as those that mediate mRNA production and translation. However, a global view of the effects of Ad5 infection on such programs in normal human cells is not available, despite widespread efforts to develop adenoviruses for therapeutic applications.


RESULTS
We used two-color hybridization and oligonucleotide microarrays to monitor changes in cellular RNA concentrations as a function of time after Ad5 infection of quiescent, normal human fibroblasts. We observed that the expression of some 2,000 genes, about 10% of those examined, increased or decreased by a factor of two or greater following Ad5 infection, but were not altered in mock-infected cells. Consensus k-means clustering established that the temporal patterns of these changes were unexpectedly complex. Gene Ontology terms associated with cell proliferation were significantly over-represented in several clusters. The results of comparative analyses demonstrate that Ad5 infection induces reversal of the quiescence program and recapitulation of the core serum response, and that only a small subset of the observed changes in cellular gene expression can be ascribed to well characterized functions of the viral E1A and E1B proteins.


CONCLUSIONS
These findings establish that the impact of adenovirus infection on host cell programs is far greater than appreciated hitherto. Furthermore, they provide a new framework for investigating the molecular functions of viral early proteins and information relevant to the design of conditionally replicating adenoviral vectors.
Miller
Daniel L
DL
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA. danielm@princeton.edu
Myers
Chad L
CL
Rickards
Brenden
B
Coller
Hilary A
HA
Flint
S Jane
SJ
D000256:Adenoviridae / Q000145:classification / Q000378:metabolism / Q000472:pathogenicity*; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D016000:Cluster Analysis; D005347:Fibroblasts / Q000166:cytology / Q000821:virology; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D016678:Genome; D006367:HeLa Cells; D006801:Humans; D007700:Kinetics; D009693:Nucleic Acid Hybridization; D020411:Oligonucleotide Array Sequence Analysis; D012313:RNA / Q000378:metabolism; D014764:Viral Proteins / Q000502:physiology
D014764:Viral Proteins; D012313:RNA