Unravelling the Evil - the role of CXCL-10 antagonist in HIV+ failing immune recovery despite cART
Although highly active antiretroviral therapy (HAART) leads in general to CD4+ T-cell recovery and decrease of general immune activation, therefore improving individuals’ long-term prognosis, in a clinically significant percentage of 20% of HIV-infected individuals CD4+ T-cell count does not increase upon HAART initiation despite complete suppression of HIV and immune activation markers remain significantly elevated – these individuals are called immunological non-responders. Recent reports have identified chemokine CXCL-10 elevation to be associated with immunological non-response. CXCL-10 directly interacts with activated T-cells enhancing pathogen-specific T-cell migration und function in an interferon-γ dependent positive feedback loop. Therefore elevated CXCL-10 expression would have been thought to be beneficial for the T-cell response, but the contrary has been observed in vivo: in immunological non-responders HIV-specific T-cell responses are lost or functionally impaired. The recent discovery of a competitive antagonistic CXCL-10 form may shed light on this obvious paradoxon.
We hypothesise that immunological non-responders will have higher antagonistic CXCL-10 titres contributing excessively to the elevation of measured total CXCL-10, possibly disrupting the positive CXCL-10 – IFN-γ feedback loop and adversely interfering with beneficial pathogen-specific immune responses in a competitive way. Furthermore dipetidyl peptidase (DPP) IV activity responsible for agonist CXCL-10 cleavage resulting in the antagonist form will be increased in HIV-positive immunological non-responders. Additionally we propose to evaluate CXCL-10 receptor (CXCR-3) distribution on T-cell subsets and CXCR-3+ T-cell functionality in the presence or absence of antagonistic CXCL-10 ex vivo and in vitro.If the hypothesis tested in this preliminary proves valid our findings may have implications for HIV-associated immune activation diagnostics (CXCL-10 antagonist form being a possible predictive factor for poor immune recovery), HIV-treatment of immunological non-responders (with addition of DPP IV inhibitors), and the fundamental understanding of the mechanisms leading to chronic immune activation observed in chronically HIV-infected individuals.
|type of project||fundamental research|
|start of project||2013|
|end of project||2014|
|project manager||Matthias Hoffmann|