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Thymidylate synthase (TS) is a key enzyme in nucleotide biosynthesis. A study performed by our group on human monocyte-derived macrophages (MDMs) infected with HIV-1 showed that many enzymes related to the folate cycle pathway, such as TS, are upregulated in productively infected cells. Here, we suggest that TS is essential for an effective HIV-1 infection in MDMs. Indeed, a TS specific small interfering RNA (siRNA) as well as the TS specific inhibitor Raltitrexed (RTX) caused a reduction in productively infected cells. Quantitative PCR analysis showed that this treatment decreased the efficacy of the early steps of the viral cycle. The RTX inhibitory effect was counteracted by dNTP addition. These results suggest that TS is essential for the early stages of HIV-1 infection by providing optimal dNTP concentrations in MDMs. TS and its related pathway may thus be considered as a potential therapeutic target for HIV-1 treatment.

Titel:	Thymidylate synthase is essential for efficient HIV-1 replication in macrophages.
Autor/in / Beteiligte Person:	Desrosiers, V ; Barat, C ; Breton, Y ; Ouellet, M ; Tremblay, MJ
Zeitschrift:	Virology, Jg. 561 (2021-09-01), S. 47-57
Veröffentlichung:	New York, Academic Press., 2021
Medientyp:	academicJournal
ISSN:	1096-0341 (electronic)
DOI:	10.1016/j.virol.2021.05.002
Schlagwort:	Cells, Cultured Enzyme Inhibitors Humans Quinazolines pharmacology RNA Interference RNA, Small Interfering SAM Domain and HD Domain-Containing Protein 1 metabolism Thiophenes pharmacology Thymidylate Synthase antagonists & inhibitors Thymidylate Synthase genetics Thymine Nucleotides metabolism HIV-1 physiology Macrophages enzymology Macrophages virology Thymidylate Synthase metabolism Virus Replication drug effects
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, Non-U.S. Gov't Language: English [Virology] 2021 Sep; Vol. 561, pp. 47-57. <i>Date of Electronic Publication: </i>2021 Jun 14. MeSH Terms: Virus Replication* / drug effects ; HIV-1 / physiology ; Macrophages / enzymology ; Macrophages / virology ; Thymidylate Synthase / metabolism ; Cells, Cultured ; Enzyme Inhibitors ; Humans ; Quinazolines / pharmacology ; RNA Interference ; RNA, Small Interfering ; SAM Domain and HD Domain-Containing Protein 1 / metabolism ; Thiophenes / pharmacology ; Thymidylate Synthase / antagonists & inhibitors ; Thymidylate Synthase / genetics ; Thymine Nucleotides / metabolism Contributed Indexing: Keywords: HIV-1; MDMs; Nucleotides; Reverse transcription; Thymidine synthase Substance Nomenclature: 0 (Enzyme Inhibitors) ; 0 (Quinazolines) ; 0 (RNA, Small Interfering) ; 0 (Thiophenes) ; 0 (Thymine Nucleotides) ; EC 2.1.1.45 (TYMS protein, human) ; EC 2.1.1.45 (Thymidylate Synthase) ; EC 3.1.5.- (SAM Domain and HD Domain-Containing Protein 1) ; EC 3.1.5.- (SAMHD1 protein, human) ; FCB9EGG971 (raltitrexed) ; QOP4K539MU (thymidine 5'-triphosphate) Entry Date(s): Date Created: 20210619 Date Completed: 20211223 Latest Revision: 20211223 Update Code: 20231215

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Thymidylate synthase is essential for efficient HIV-1 replication in macrophages.