DOWN-MODULATION OF CELL-SURFACE EXPRESSION OF P80 FORM OF THE TUMOR-NECROSIS-FACTOR RECEPTOR BY HUMAN IMMUNODEFICIENCY VIRUS-1 TAT GENE

Tumor necrosis factor-alpha (TNF-alpha) induces the expression of human immunodeficiency virus type-1 (HIV-1) in vitro in chronically infected cells of T and monocytic origin. The tat protein from the HIV-1 virus has been shown to be essential for HIV replication and in the immunosuppression associated with the virus infection. Previous studies in our laboratory have shown that HIV-1 tat gene induces TNF-beta (lymphotoxin) in human B-lymphoblastoid cells (Sastry et al., 1990, J. Biol. Chem. 265, 20091-20093). In an attempt to characterize further the relationship between the host and HIV-1, we investigated the effect of the functional HIV-1 tat gene on the expression of TNF receptors in a human B lymphoblastoid cell line (Raji). We report here that Raji cells transfected with HIV-1 tat gene express fewer cell surface TNF receptors than control cells. At least a 5-fold decrease in the receptor number without any significant change in receptor affinity was observed. The decrease in TNF receptors in tat-transfected Raji cells (Raji-tat cells) was found not to be due to receptor occupancy by the autocrine production of TNF-beta. The decrease in the cell surface expression of TNF receptors in Raji-tat cells was also found to be not due to a decrease in the gene expression of the receptor. The kinetics, amount of TNF binding and its internalization were temperature dependent, and it was different in Raji-tat cells than in the control cells. In spite of the low number of cell surface TNF receptors, the HIV-1 tat-transfected cells retained their high rate of internalization of TNF-alpha (they bound 20 times more TNF-alpha at 37-degrees-C than at 4-degrees-C by 6 h) perhaps because of enhanced recycling and/or turnover of the receptors. The HIV-1 tat gene had no effect on the degradation pattern of TNF-alpha. Among the p60 and p80 forms of the TNF receptors recently identified, only the p80 form was found in both control and Raji-tat cells. The importance of the downregulation of TNF receptors by HIV-1 tat in immunosuppression observed during HIV infection is discussed.