SOLUBLE TUMOR-NECROSIS-FACTOR RECEPTORS INHIBIT PHORBOL-MYRISTATE ACETATE AND CYTOKINE-INDUCED HIV-1 EXPRESSION CHRONICALLY INFECTED U1 CELLS

Recombinant human tumor necrosis factor (TNF) binding protein-1 (r-hTB P-1) and recombinant human soluble dimeric TNF receptor (rhu TNFR:Fc) were used to determine the relative contributions of TNF to phorbol my ristate acetate (PMA) and cytokine-induced human immunodeficiency viru s type I (HIV-1) replication in chronically infected cell lines. Treat ment of HIV-1-infected promonocytic U1 cells with r-hTBP-1 or rhu TNFR :Fc reduced PMA-induced HIV-1 p24 antigen production in a concentratio n-dependent manner, with a maximal inhibition of approximately 90%. Ma ximal inhibition of p24 antigen production in T-lymphocytic ACH-2 cell s was 47% with r-hTBP-1 and 42% with rhu TNFR:Fc. r-hTBP-1 and rhu TNF R:Fc also decreased p24 antigen synthesized by U1 cells in response to other stimuli, including phytohemagglutinin (PHA)-induced supernatant , granulocyte-macrophage colony-stimulating factor, interleukin-h, and TNF. Addition of r-hTBP-1 to UI cells during the last 4 h of a 24 h i ncubation with PMA still inhibited p24 antigen production by 15%. U1 c ells stimulated with 10(-7) M PMA released similar to 1 ng/ml endogeno us TBP-1 with an initial peak observed at I h and a second peak at 24 h after PMA stimulation. r-hTBP-1 also partially reversed inhibition o f U1 cellular proliferation caused by PMA. Both r-hTBP-1 and rhu TNFR: Fc blocked PMA induction of nuclear factor (NK)-kappa B DNA-binding ac tivity in U1 cells in association with decreases in HIV-1 replication. We conclude that soluble TNF receptors can inhibit stimuli-induced HI V-1 expression and NF-kappa B DNA-binding activity in chronically infe cted U1 cells.