Soluble Tumor Necrosis Factor Receptor: Inhibition of Human Immunodeficiency Virus Activation

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 90; no. 6; pp. 2335 - 2339
• Main Authors: O. M. Zack Howard, Clouse, Kathleen A., Smith, Craig, Goodwin, R. G., Farrar, William L.
• Format: Journal Article
• Language: English
• Published: Washington, DC National Academy of Sciences of the United States of America 15.03.1993; National Acad Sciences; National Academy of Sciences
• Subjects: activation; Analysis of the immune response. Humoral and cellular immunity; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line; Cell lines; Cellular biology; Chloramphenicol O-Acetyltransferase - genetics; Chloramphenicol O-Acetyltransferase - metabolism; Cultured cells; Cytokines; Dimers; Dose-Response Relationship, Drug; Fundamental and applied biological sciences. Psychology; Fundamental immunology; HIV; HIV 1; HIV Long Terminal Repeat; HIV Reverse Transcriptase; HIV-1 - drug effects; HIV-1 - growth & development; HIV-1 - physiology; Human immunodeficiency virus; Humans; Immunity (Disease); Immunobiology; Immunoglobulin G - genetics; Immunoglobulin G - pharmacology; Immunoglobulin Heavy Chains - genetics; Immunoglobulin Heavy Chains - pharmacology; inhibition; long terminal repeat; Miscellaneous; Receptors; Receptors, Cell Surface - genetics; Receptors, Tumor Necrosis Factor; Recombinant Fusion Proteins - metabolism; Recombinant Fusion Proteins - pharmacology; Regulatory factors and their cellular receptors; RNA-Directed DNA Polymerase - metabolism; Solubility; T lymphocytes; Teeth; transcription; Trimers; Tumor Necrosis Factor-alpha - pharmacology; tumor necrosis factors; Tumors; Virus Activation - drug effects; Human; Immunoglobulins; Virus multiplication; Monocyte; HIV-1 virus; heavy-Peptide chain; Cytokine; Retroviridae; Molecular hybrid; IgG1; Soluble form; Gene expression; Virus; T-Lymphocyte; Lentivirinae; Human immunodeficiency virus; Infected cell; Inhibition; Recombinant protein; Tumor necrosis factor α; Biological receptor
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.6.2335

The inflammatory cytokine tumor necrosis factor α (TNF-α) has been shown to stimulate human immunodeficiency virus type 1 (HIV-1) replication in both chronically and acutely infected T lymphocytes and monocytes. Transcriptional activation of the HIV long terminal repeat and subsequent increase in virus production are linked to TNF activation of the cellular transcription factor NF-κ B. Here we report the use of two forms of soluble recombinant type 1 (p80) TNF receptor to inhibit TNF-induced HIV activation in vitro. One receptor form is a monomer containing the entire 236 residues of the extracellular (ligand-binding) portion of p80. A second receptor form is a chimeric homodimer containing these residues fused to a truncated human IgG1 immunoglobulin heavy chain and, thus, resembles a bivalent antibody without light chains. These recombinant receptor proteins were tested for their ability to inhibit TNF-α-induced expression of HIV-1 in chronically infected human cell lines. We also examined the ability of the soluble receptors to limit the activation of the HIV-long terminal repeat transcription. The soluble TNF receptor dimer was most effective at blocking TNF-α-induced HIV-1 expression in both monocytoid and lymphoid cells. The molar ratio of TNF-receptor dimer to TNF-α found to be most effective was, at least, 5:1. We conclude that at specific TNF/soluble TNF-receptor dimer ratios, TNF-α-induced HIV-1 transcription and expression can be limited in vitro.