The cellular and molecular pathways involved in the regulatory effects of proinflammatory and immunoregulatory cytokines on human immunodeficiency virus (HIV) expression/replication were investigated. The central role of endogenous proinflammatory cytokines, particularly interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha, in driving HIV replication in acutely infected peripheral blood mono-nuclear cells (PBMC) stimulated with IL-2 was demonstrated. Various physiologic cytokine inhibitors were found to suppress HIV replication in this system by interfering with the autocrine/paracrine loop of cytokine mediated stimulation of HIV production. Bacterial lipopolysaccharide (LPS), a physiologic stimulator of proinflammatory cytokine production by monocytic cells, was shown to induce HIV expression in a chronically infected monocytic cell line (U1) and this effect was demonstrated to be dependent upon the stimulation of an autocrine/paracrine loop involving endogenous IL-1beta. Anti-proinflammatory cytokines, such as transforming growth factor (TGF)-beta, IL-4, and IL-13, and IL-1 receptor antagonist (ra), inhibited LPS-induced HIV expression primarily by suppressing IL- 1beta and increasing IL-1ra production. Proinflam-matory cytokines were also evaluated for their effect on ex vivo HIV replication. IL-1-beta, IL-6 and TNF-alpha were found to enhance HIV production by MC of certain HIV-infected subjects. Cross-linking of CD30 on the surface of HIV- infected cells by CD30-CD30 ligand interactions induced HIV expression by a TNF-independent, NF-kappaB dependent pathway. The ability of various immunoregulatory cytokines, such as interleukin (IL)-2 and IL-12, were evaluated with regard to their relative stimulatory effects on HIV production by CD4+ T cells versus their ability to stimulate CD8-mediated nonlytic viral suppressor (CD8s) activity in lymph node (LN) and PBMC from HIV-infected subjects. IL-2 potently stimulated CD8s, an effect which overrode its inductive effect on HIV production, resulting in an inability to isolate virus in the presence of CD8+ cells. Other immunoregulatory cytokines, such as IL-12, were not as effective in inducing CD8s and thus allowed viral replication in the presence of CD8+ cells. PBMC from HIV-infected subjects undergoing IL-2/AZT combination therapy are being analyzed for evidence of IL-2 induced increases in CD8s activity. These studies demonstrate the complex interactions between cytokines and HIV replication/expression, involving both direct modulation of virus production from infected cells or indirect regulation via stimulation of host anti-viral activities.
