We had previously demonstrated the phenomenon and the mechanisms of the regulation of human immunodeficiency virus (HIV) expression by endogenous cytokines. In addition, we had previously determined that the lymphoid organs are the major sites of HIV burden and expression at all stages of disease. We currently have examined the constitutive expression of a panel of cytokines (interleukin [IL]-1beta, tumor necrosis factor [TNF- alpha], IL-6, IL-2, interferon [IFN]-gamma, IL-4, and IL-10) in the peripheral blood (PB) and lymph node (LN) mononuclear cells (MC) of HIV- infected individuals at various stages of disease. We demonstrated that TNF-alpha, IL-6, IFN-gamma and IL-10 were hyper-expressed in the LNMC and PBMC of HIV-infected compared to uninfected individuals; IL-1beta was overexpressed only in the PBMC. These observations are likely to be a reflection of the state of heightened immune activation in HIV infection. Since several of these cytokines have been demonstrated to induce HIV, this over-expression may play a role in the persistent induction of HIV in the milieu of the LN that increases with disease progression. Despite the state of heightened immune activation, IL-2 and IL-4 were poorly expressed at all stages of disease. This dysregulation of cytokine expression may contribute to the immune defects in HIV disease. Contrary to previous reports, in studies involving cross-sectional (among different patients) and longitudinal (within individual patients) analyses, we did not observe a """"""""switch"""""""" in predominance from Th-1 (IL-2, IFN-gamma) to Th-2 (IL-4, IL-10) patterns of constitutive cytokine expression as disease progressed. Pattern switches were also not observed upon stimulation of cells. In addition, studies on sorted populations of CD4+, CD4-, CD8+, and CD8- cell subsets demonstrated that even early in the course of disease CD4+ T cell subsets constitutively express very low levels of cytokines. The increased expression of IL-10 and IFN-gamma was found largely in the CD8+ T cell subsets and among B cells and monocytes. These studies may add insight into our understanding of the immunopathogenesis of HIV disease and may provide potential targets for therapeutic intervention.
