Human cytomegalovirus stimulates cellular dihydrofolate reductase activity in quiescent cells.
Human cytomegalovirus (HCMV) productively infects quiescent fibroblasts in which the levels of deoxynucleotide triphosphates (dNTPs) and cell functions involved in DNA metabolism are very low. Since sufficient dNTPs levels are essential for human HCMV replication, host cell enzymes involved in the biosynthesis of dNTPs might be expected to be stimulated by viral infection in quiescent cells. We report that HCMV infection of quiescent fibroblasts stimulates the activity of cellular dihydrofolate reductase (DHFR), a key enzyme in DNA precursor synthesis. We also demonstrate that suppression of DHFR activity by the specific inhibitor methotrexate prevents HCMV replication and DNA synthesis. These observations indicate that induction of DHFR activity by HCMV is required for efficient viral replication in quiescent fibroblasts.
Department of Public Health and Microbiology, University of Torino, Torino, Italy.
D
D
Lembo
G
G
Gribaudo
R
R
Cavallo
L
L
Riera
A
A
Angeretti
L
L
Hertel
S
S
Landolfo
D002478:Cells, Cultured / Q000201:enzymology / Q000821:virology; D003587:Cytomegalovirus / Q000254:growth & development / Q000378:metabolism*; D004279:DNA, Viral / Q000096:biosynthesis / Q000187:drug effects; D004789:Enzyme Activation; D005493:Folic Acid Antagonists / Q000494:pharmacology; D006801:Humans; D008727:Methotrexate / Q000494:pharmacology; D013762:Tetrahydrofolate Dehydrogenase / Q000378:metabolism*; D013997:Time Factors; D014779:Virus Replication
D004279:DNA, Viral; D005493:Folic Acid Antagonists; D013762:Tetrahydrofolate Dehydrogenase; D008727:Methotrexate