title: Evaluation of the effect of pyrimethamine, an anti-malarial drug, on HIV-1 replication.
abstract: Co-infection of human immunodeficiency virus (HIV) with malaria is one of the pandemic problems in Africa and parts of Asia. Here we investigated the impact of pyrimethamine (PYR) and two other clinical anti-malarial drugs (chloroquine [CQ] or artemisinin [ART]) on HIV-1 replication. Peripheral blood mononuclear cells (PBMCs) or MT-2 cells were infected with HIV(NL4.3) strain and treated with different concentrations of the anti-malarial drugs. HIV-1 replication was measured using p24 ELISA. We show that 10 μM CQ and ART inhibited HIV-1 replication by 76% and 60% in PBMCs, respectively, but not in MT-2 cells. In contrast, 10 μM PYR enhanced HIV-1 replication in MT-2 cells by >10-fold. A series of molecular mechanism studies revealed that PYR increased intracellular HIV gag proteins without affecting the promoter or the reverse transcriptase activity. The effect of PYR was independent of HTLV-1 produced by MT-2 cells. Of interest, PYR treatment led to S-phase accumulation and increased AZT and d4T antiviral activity by ∼ 4-fold. Taken together, we show that PYR significantly enhances HIV-1 replication by affecting the cellular machinery. Our results could be relevant for the management of malaria and HIV particularly in regions where HIV-1 and malaria epidemics overlap.
authors.affiliation: Laboratory of Human Retrovirology, Science Applications International Corporation-Frederick, Inc., National Cancer Institute at Frederick, Frederick, MD 21702, USA. oguaririr@mail.nih.gov
authors.forename: Raphael M
authors.initials: RM
authors.lastname: Oguariri
authors.forename: Joseph W
authors.initials: JW
authors.lastname: Adelsberger
authors.forename: Michael W
authors.initials: MW
authors.lastname: Baseler
authors.forename: Tomozumi
authors.initials: T
authors.lastname: Imamichi
mesh_terms: D000962:Antimalarials / Q000494:pharmacology*; D000998:Antiviral Agents / Q000494:pharmacology*; D037621:Artemisinins / Q000494:pharmacology; D002478:Cells, Cultured; D002738:Chloroquine / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D016655:HIV Core Protein p24 / Q000032:analysis; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008214:Lymphocytes / Q000821:virology; D011739:Pyrimethamine / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000962:Antimalarials; D000998:Antiviral Agents; D037621:Artemisinins; D016655:HIV Core Protein p24; D002738:Chloroquine; C031327:artemisinin; D011739:Pyrimethamine
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