title: A soluble factor(s) secreted from CD8(+) T lymphocytes inhibits human immunodeficiency virus type 1 replication through STAT1 activation.
abstract: CD8(+) T lymphocytes can suppress human immunodeficiency virus type 1 (HIV-1) replication by secreting a soluble factor(s) known as CD8(+) T-lymphocyte antiviral factor (CAF). One site of CAF action is inhibition of HIV-1 RNA transcription, particularly at the step of long terminal repeat (LTR)-driven gene expression. However, the mechanism by which CAF inhibits LTR activation is not understood. Here, we show that conditioned media from several herpesvirus saimari-transformed CD8(+) T lymphocytes inhibit, in a time- and dose-dependent manner, the replication of HIV-1 pseudotype viruses that express the envelope glycoproteins of vesicular stomatitis virus (HIV-1(VSV)). The same conditioned media also inhibit phorbol myristate acetate-induced activation of the HIV-1 LTR and activate the signal transducer and activator of transcription 1 (STAT1) protein. We have obtained direct evidence that STAT1 is necessary for CAF-mediated inhibition of LTR activation and HIV-1 replication. Thus, the inhibitory effect of CAF on HIV-1(VSV) replication was abolished in STAT1-deficient cells. Moreover, CAF inhibition of LTR activation was diminished both in STAT1-deficient cells and in cells expressing a STAT1 dominant negative mutant but was restored when STAT1 was reintroduced into the STAT1-deficient cells. We also observed that CAF induced the expression of interferon regulatory factor 1 (IRF-1), and that IRF-1 gene induction was STAT-1 dependent. Taken together, our results suggest that CAF activates STAT1, leading to IRF-1 induction and inhibition of gene expression regulated by the HIV-1 LTR. This study therefore helps clarify one molecular mechanism of host defense against HIV-1.
authors.affiliation: Weill Medical College of Cornell University, Department of Medicine, Mount Sinai School of Medicine, Public Health Research Institute, New York, New York 10021, USA.
authors.forename: Theresa Li-Yun
authors.initials: TL
authors.lastname: Chang
authors.forename: Arevik
authors.initials: A
authors.lastname: Mosoian
authors.forename: Richard
authors.initials: R
authors.lastname: Pine
authors.forename: Mary E
authors.initials: ME
authors.lastname: Klotman
authors.forename: John P
authors.initials: JP
authors.lastname: Moore
mesh_terms: D001685:Biological Factors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002461:Cell Line, Transformed; D017077:Culture Media, Conditioned / Q000737:chemistry / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D024202:Electrophoretic Mobility Shift Assay; D015967:Gene Expression Regulation, Viral / Q000187:drug effects; D005799:Genes, Dominant / Q000235:genetics; D016325:HIV Long Terminal Repeat / Q000235:genetics; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006367:HeLa Cells; D006567:Herpesvirus 2, Saimiriine / Q000502:physiology; D006801:Humans; D050856:Interferon Regulatory Factor-1; D007371:Interferon-gamma / Q000032:analysis; D009154:Mutation / Q000235:genetics; D010750:Phosphoproteins / Q000096:biosynthesis / Q000378:metabolism; D011485:Protein Binding; D050794:STAT1 Transcription Factor; D012995:Solubility; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013997:Time Factors; D015534:Trans-Activators / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D015533:Transcriptional Activation / Q000187:drug effects; D014162:Transfection; D014779:Virus Replication / Q000187:drug effects
chemical_list: D001685:Biological Factors; D017077:Culture Media, Conditioned; D004268:DNA-Binding Proteins; C494257:IRF1 protein, human; D050856:Interferon Regulatory Factor-1; D010750:Phosphoproteins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D015534:Trans-Activators; D007371:Interferon-gamma; D013755:Tetradecanoylphorbol Acetate