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-κB activation

Abstract

Tumor necrosis factor (TNF)-α controls T-cell activation and is a major inducer of human immunodeficiency virus (HIV)-1 replication in chronically infected cells. Therefore, we have investigated its role in primary cultures of HIV-infected human T lymphocytes by using neutralizing anti–TNF-α antibodies or TNF-α. Primary resting T lymphocytes produced TNF-α and supported HIV replication after T-cell receptor activation. Addition of neutralizing anti– TNF-α antibodies drastically reduced p24 antigen release and prevented CD4 + cell depletion associated with infection. Anti–TNF-α also prevented nuclear factor-κB (NF-κB) activation, and a good correlation between this inhibition and inhibition of HIV replication was observed. Moreover, supplementing the cultures with high doses of IL-2 reverted anti–TNF-α inhibition of cell proliferation but did not affect the inhibition of HIV p24 antigen release or NF-κB activation in the same cultures. Moreover, anti–TNF-α inhibited HIV-1 long terminal repeat (LTR)-driven transcription of a reporter gene in primary T cells in response to activation, either in the presence or the absence of HIV-1 Tat. Our results support an important role for autocrine TNF-α secretion in controlling HIV replication in primary T cells because of its ability to maintain NF-κB elevated in the nucleus of T cells. (J Allergy Clin Immunol 1997;100:838-45.)