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Proc Natl Acad Sci U S A. 2013 Dec 17;110(51):E5006-15. doi: 10.1073/pnas.1321305110. Epub 2013 Dec 2.

Argininosuccinate synthetase 1 depletion produces a metabolic state conducive to herpes simplex virus 1 infection.

Author information

1
Departments of Molecular Biology and Chemistry, and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ 08544.

Abstract

Herpes simplex virus 1 (HSV-1) infection triggers specific metabolic changes in its host cell. To explore the interactions between cellular metabolism and HSV-1 infection, we performed an siRNA screen of cellular metabolic genes, measuring their effect on viral replication. The screen identified multiple enzymes predicted to influence HSV-1 replication, including argininosuccinate synthetase 1 (AS1), which consumes aspartate as part of de novo arginine synthesis. Knockdown of AS1 robustly enhanced viral genome replication and the production of infectious virus. Using high-resolution liquid chromatography-mass spectrometry, we found that the metabolic phenotype induced by knockdown of AS1 in human fibroblasts mimicked multiple aspects of the metabolic program observed during HSV-1 infection, including an increase in multiple nucleotides and their precursors. Together with the observation that AS1 protein and mRNA levels decrease during wild-type infection, this work suggests that reduced AS1 activity is partially responsible for the metabolic program induced by infection.

KEYWORDS:

herpesviruses; metabolomics

PMID:
24297925
PMCID:
PMC3870743
DOI:
10.1073/pnas.1321305110
[Indexed for MEDLINE]
Free PMC Article
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