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During infection viruses hijack host cell metabolism to promote their replication. Here, analysis of metabolite alterations in macrophages exposed to poly I:C recognises that the antiviral effector Protein Kinase RNA-activated (PKR) suppresses glucose breakdown within the pentose phosphate pathway (PPP). This pathway runs parallel to central glycolysis and is critical to producing NADPH and pentose precursors for nucleotides. Changes in metabolite levels between wild-type and PKR-ablated macrophages show that PKR controls the generation of ribose 5-phosphate, in a manner distinct from its established function in gene expression but dependent on its kinase activity. PKR phosphorylates and inhibits the Ribose 5-Phosphate Isomerase A (RPIA), thereby preventing interconversion of ribulose- to ribose 5-phosphate. This activity preserves redox control but decreases production of ribose 5-phosphate for nucleotide biosynthesis. Accordingly, the PKR-mediated immune response to RNA suppresses nucleic acid production. In line, pharmacological targeting of the PPP during infection decreases the replication of the Herpes simplex virus. These results identify an immune response-mediated control of host cell metabolism and suggest targeting the RPIA as a potential innovative antiviral treatment. Synopsis: Although the cellular immune response controls metabolism to try to limit viral infection, the mechanisms involved remain poorly understood. This study identifies the antiviral effector RNA-activated protein kinase PKR as a control factor for glucose breakdown in the pentose phosphate pathway (PPP), limiting pentose precursor generation, nucleic acid synthesis and viral proliferation. Antiviral response by PKR alters cellular glucose metabolism, limiting ribose 5-phosphate production in the non-oxidative PPP. PKR-mediated control of the PPP is kinase function-dependent but distinct from its role in gene expression. PKR phosphorylates Ribose 5-Phosphate Isomerase A (RPIA), suppressing ribose 5-phosphate production. Pharmaceutical targeting of the PPP limits Herpes simplex virus replication. RNA-activated protein kinase counters viral infection by suppressing a pentose phosphate pathway precursor required for virus genome replication. [ABSTRACT FROM AUTHOR]