Human immunodeficiency virus infection is a chronic condition causing significant changes in the immune system, which are reflected in the altered gene expression patterns of the immune cells. By studying these patterns through gene expression profiling it is possible to describe not only the current states the cells are in, but also to extrapolate the proximal signals that resulted in the observed patterns. In the studies described herein, we have applied this approach to better understand the alterations in the immune function that occur in HIV infection. First, we have obtained transcriptional profiles of CD4+ and CD8+ T cells from patients in early infection, in chronic infection, and in non-progressive infection, and we compared these profiles to each other and to the profiles from uninfected donors. The analyses of the profiles revealed no discernable changes in the T cells of the non-progressive patients when compared to the uninfected individuals. On the other hand, T cells from patients with progressive infection, both early and late, showed patterns characteristic of type I interferon (IFN) exposure. We next examined experimentally the possible proximal causes of the observed transcriptional profiles. We analyzed the gene expression patterns induced by TGFβ, 13 type I interferons, as well as recombinant HIV Tat protein, in T cells and peripheral blood mononuclear cells. The TGFβ responses were inconsistent with the transcriptional profiles seen in HIV-infected patients, whereas both type I IFNs and HIV Tat induced genes in patterns consistent with those seen in patients. In fact, the thirteen IFN-induced patterns were indistinguishable from each other. Tat treatments induced interferon-stimulated genes (ISGs) as well as other genes and the response was not dependent on the presence of plasmacytoid dendritic cells (pDCs), suggesting monocytes as the possible source of the interferon response. In the last study, we examined the responses of plasmacytoid dendritic cells (pDCs) to HIV and other stimuli in healthy and HIV-infected subjects. We observed induction of IFN genes in pDCs of all subjects in response to influenza virus and TLR7 agonist imiquimod, but not to HIV virus. In summary, HIV infection results in chronic induction of type I IFN response in cells of the immune system. The source of this response is likely to be type I IFNs produced by monocytes/macrophages rather than plasmacytoid cells. The monocytic production of type I IFN may be a Tat-dependent response.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/26459 |
| Date | 07 March 2011 |
| Creators | Hyrcza, Martin Dominik |
| Contributors | Der, Sandy D. |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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