Thioredoxin reductase-1 negatively regulates HIV-1 transactivating protein Tat-dependent transcription in human macrophages.
Epidemiological studies suggest a correlation between severity of acquired immunodeficiency syndrome (AIDS) and selenium deficiency, indicating a protective role for this anti-oxidant during HIV infection. Here we demonstrate that thioredoxin reductase-1 (TR1), a selenium-containing pyridine nucleotide-disulfide oxidoreductase that reduces protein disulfides to free thiols, negatively regulates the activity of the HIV-1 encoded transcriptional activator, Tat, in human macrophages. We used a small interfering RNA approach as well as a high affinity substrate of TR1, ebselen, to demonstrate that Tat-dependent transcription and HIV-1 replication were significantly increased in human macrophages when TR1 activity was reduced. The increase in HIV-1 replication in TR1 small interfering RNA-treated cells was independent of the redox-sensitive transcription factor, NF-kappaB. These studies indicate that TR-1 acts as a negative regulator of Tat-dependent transcription. Furthermore, in vitro biochemical assays with recombinant Tat protein confirmed that TR1 targets two disulfide bonds within the Cys-rich motif required for efficient HIV-1 transactivation. Increasing TR1 expression along with other selenoproteins by supplementing with selenium suggests a potential inexpensive adjuvant therapy for HIV/AIDS patients.
Center for Molecular Immunology and Infectious Disease, The Pennsylvania State University, University Park, Pennsylvania 16802, USA.
Parisa
P
Kalantari
Vivek
V
Narayan
Sathish K
SK
Natarajan
Kambadur
K
Muralidhar
Ujjawal H
UH
Gandhi
Hema
H
Vunta
Andrew J
AJ
Henderson
K Sandeep
KS
Prabhu
D000163:Acquired Immunodeficiency Syndrome / Q000276:immunology / Q000378:metabolism*; D020816:Amino Acid Motifs / Q000502:physiology; D015967:Gene Expression Regulation, Viral / Q000187:drug effects / Q000502:physiology*; D015497:HIV-1 / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects / Q000502:physiology; D008264:Macrophages / Q000201:enzymology* / Q000276:immunology / Q000821:virology; D016328:NF-kappa B / Q000276:immunology / Q000378:metabolism; D010084:Oxidation-Reduction; D034741:RNA, Small Interfering / Q000494:pharmacology; D012643:Selenium / Q000494:pharmacology; D054481:Thioredoxin Reductase 1 / Q000276:immunology / Q000378:metabolism*; D014158:Transcription, Genetic / Q000187:drug effects / Q000276:immunology; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology*; D020298:U937 Cells; D014779:Virus Replication / Q000502:physiology; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000276:immunology / Q000378:metabolism*
D016328:NF-kappa B; D034741:RNA, Small Interfering; D054322:tat Gene Products, Human Immunodeficiency Virus; C516124:TXNRD1 protein, human; D054481:Thioredoxin Reductase 1; D012643:Selenium