Masters Thesis

HIV infection causes cytokine dysregulation in the thymus

Modification of cytokine expression is one means by which human immunodeficiency virus (HIV) could attenuate normal immune responses, including those generated against HIV itself. Aberrant cytokine expression may precede and even stimulate pathophysiological abnormalities associated with HIV infection. Alternatively, abnormal cytokine expression may accompany disease progression without influencing HIV pathogenesis. In the search for effective new HIV therapies, it is therefore important to determine the relationship between cytokine dysregulation and the immunopathogenesis of HIV infection. To date, analysis of HIV-infected blood samples from the patient population and cells infected in vitro have revealed upregulated expression of interleukin 6 (IL-6), IL-10, tumor necrosis factor (TNFa), and transforming growth factor (TGFB). and decreased concentrations of IL-2 and IL-12. On the basis of these findings, it has been postulated that HIV infection induces the immune system to switch from a T helper- 1 cell-mediated immune response (TH1) to a humoral immune response (TH2). This switch would involve decreased IL-2 and IFNy production and augmented IL-4, IL-6 and IL-10 synthesis. To address the relationship of cytokine expression and HIV infection in the thymus, we have examined cytokine concentrations following infection with HIV in both the SCID-hu Thy/Liv mouse model and in a human fetal thymus organ culture system (TOC). Both the in vivo and in vitro models exhibit similar parameters of HIV-associated pathology, including time-dependent viral replication, thymocyte depletion, and inversion of the CD4/CD8 ratio. Following HIV infection in both of these models, IL-2 expression was diminished, while expression levels of lL-4, lL-6, IL-10, TNFa, and TGFB were enhanced. We were unable to measure a consistent alteration in either lL-12 or IFNy expression, and IL-7 concentrations were not modified by HIV infection. These findings support the hypothesis of a TH1 to TH2 switch following HIV infection and may suggest potential cytokine or cytokine modifying therapies.

Items in ScholarWorks are protected by copyright, with all rights reserved, unless otherwise indicated.