REPLICATION OF HUMAN IMMUNODEFICIENCY VIRUS-1 IN PRIMARY HUMAN T-CELLS IS DEPENDENT ON THE AUTOCRINE SECRETION OF TUMOR-NECROSIS-FACTOR THROUGH THE CONTROL OF NUCLEAR FACTOR-KAPPA-B ACTIVATION

Tumor necrosis factor (TNF)-alpha controls T-cell activation and is a major inducer of human immunodeficiency virus (HIV)-1 replication in c hronically infected cells. Therefore, we have investigated its role in primary cultures of HIV-infected human T lymphocytes by using neutral izing anti-TNF-alpha antibodies or TNF-alpha. Primary resting T lympho cytes produced TNF-alpha and supported HIV replication after T-cell re ceptor activation. Addition of neutralizing anti-TNF-alpha antibodies drastically reduced p24 antigen release and prevented CD4(+) cell depl etion associated with infection. Anti-TNF-alpha also prevented nuclear factor-kappa B (NF-kappa B) activation, and a good correlation betwee n this inhibition and inhibition of HIV replication was observed. More over, supplementing the cultures with high doses of IL-2 reverted anti -TNF-alpha inhibition of cell proliferation but did not affect the inh ibition of HIV p24 antigen release or NF-kappa B activation in the sam e cultures. Moreover, anti-TNF-alpha inhibited HIV-1 long terminal rep eat (LTR)-driven transcription of a reporter gene in primary T cells i n response to activation, either in the presence or the absence of HIV -1 Tat. Our results support an important role for autocrine TNF-alpha secretion in controlling HIV replication in primary T cells because of its ability to maintain NF-kappa B elevated in the nucleus of T cells .