Soluble tumor necrosis factor receptor: inhibition of human immunodeficiency virus activation.
The inflammatory cytokine tumor necrosis factor alpha (TNF-alpha) 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-kappa 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-alpha-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-alpha-induced HIV-1 expression in both monocytoid and lymphoid cells. The molar ratio of TNF-receptor dimer to TNF-alpha found to be most effective was, at least, 5:1. We conclude that at specific TNF/soluble TNF-receptor dimer ratios, TNF-alpha-induced HIV-1 transcription and expression can be limited in vitro.
Howard
O M
OM
Biological Carcinogenesis and Development Program, Program Resources, Inc./DynCorp, Frederick, MD.
Clouse
K A
KA
Smith
C
C
Goodwin
R G
RG
Farrar
W L
WL
D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D015500:Chloramphenicol O-Acetyltransferase / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D016325:HIV Long Terminal Repeat; D054303:HIV Reverse Transcriptase; D015497:HIV-1 / Q000187:drug effects / Q000254:growth & development / Q000502:physiology*; D006801:Humans; D007074:Immunoglobulin G / Q000235:genetics / Q000494:pharmacology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000494:pharmacology; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology*; D012995:Solubility; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D014775:Virus Activation / Q000187:drug effects
D000998:Antiviral Agents; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D011956:Receptors, Cell Surface; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D015500:Chloramphenicol O-Acetyltransferase; D054303:HIV Reverse Transcriptase; D012194:RNA-Directed DNA Polymerase