TUMOR-NECROSIS-FACTOR RECEPTOR EXPRESSION AND SIGNAL-TRANSDUCTION IN HIV-1-INFECTED CELLS

Objective: To examine the inter-relationship between HIV-1 infection and the cell surface receptors for tumor necrosis factor (TNF)-alpha, an immunoregulatory cytokine that can enhance HIV-1 replication. Design: Infected promyelocytic and promonocytic cells were examined because they normally express both types of TNF receptors. Methods: TNF receptor surface expression was determined by specific monoclonal antibody recognition and flow cytometry, and signal transduction was detected by gel shift analysis. HIV-1 activation and expression was quantitated by reverse transcriptase assay. Results: In the OM-10.1 promyelocytic model of chronic infection, TNF-alpha-induced HIV-1 expression also resulted in a substantial increase in 75 kd TNF receptor (TR75) expression although 55 kD TNF receptor (TR55) levels were not dramatically altered. A series of uninfected parental HL-60 subclones all reduced TR75 surface expression in response to TNF-alpha treatment. Enhanced TR75 expression on OM-10.1 cells followed the same TNF-alpha-dose dependency as that observed for HIV-1 production. An increase in TR75 expression was also evident during the peak of an acute HIV-1 infection of HL-60 promyelocytes. Although TR55 expression was unaltered during TNF-alpha-induced HIV activation, this receptor was still involved in the viral activation process. Antibody cross-linking of TR55, in the absence of exogenous TNF-alpha, induced maximal HIV-1 expression, an up-modulation of surface TR75, and nuclear NF-kappaB activity in OM-10.1 cultures. Surprisingly, this was the case even when an antagonistic anti-TR55 antibody was used. Anti-TR55 antibody cross-linking in chronically infected U1 promonocytic cultures could only partially substitute for TNF-alpha-induced HIV-1 expression. Conclusions: Our results demonstrated that HIV-1 infection can selectively influence the surface expression of TNF receptors, potentially influencing its own expression and altering normal immunoregulatory signal transduction.