EFFECT OF CELLULAR-DIFFERENTIATION ON CYTOKINE-INDUCED EXPRESSION OF HUMAN-IMMUNODEFICIENCY-VIRUS IN CHRONICALLY INFECTED PROMONOCYTIC CELLS - DISSOCIATION OF CELLULAR-DIFFERENTIATION AND VIRAL EXPRESSION

Cellular differentiation is thought to play an important role in the s usceptibility of monocytic lineage cells to human immunodeficiency vir us (HIV) infection as well as in their ability to support virus replic ation. In addition, virus replication in monocytes/macrophages has bee n demonstrated in vitro to be strongly modulated by several cytokines such as tumor necrosis factor alpha and granulocyte-macrophage colony- stimulating factor. The purpose of the present study was to investigat e the interaction between cellular differentiation and cytokines in th e regulation of HIV expression from chronically infected monocytic lin eage cells. U1, a persistently HIV-infected promonocytic cell line, is characterized by low levels of virus expression which can be modulate d by several cytokines. 1 alpha,-25-Dihydroxyvitamin D3 (Vit.D3), a we ll-known differentiating agent for myelomonocytic cells which has been previously reported to modulate HIV replication in other in vitro sys tems, induced maturation of U1 cells toward a macrophage-like phenotyp e, as demonstrated by the induction of the differentiation-associated cell surface markers CD14 and CD11b. Vit.D3-induced differentiation di d not result in induction of HIV expression; however, when U1 cells we re stimulated with tumor necrosis factor alpha in the presence of Vit. D3, a synergistic induction of cell differentiation and viral expressi on was demonstrated. In contrast, Vit.D3 suppressed the induction of H IV expression in U1 cells stimulated,vith gamma interferon, interleuki n-6, and granulocyte-macrophage colony-stimulating factor, although sy nergy between Vit.D3 and these cytokines was observed in terms of cell ular differentiation. These data suggest that differentiation of monoc ytic cells does not necessarily correlate with increased HIV expressio n.