Elucidation of innate immune response dysfunction of HIV patients: the underlying mechanisms amongst immunological and epigenetic modifications

Abstract

Basic researches can help to solve clinical problems, providing tools to transfer results from the bench to the bedside. In developing countries including Brazil, the HIV-1 infection is a major cause of death attributed to infectious diseases, especially when associated with opportunistic co-infections, such as tuberculosis, which affects one third of patients infected with HIV. Multiple studies have shown that macrophages derived from HIV-infected patients exhibit changes in phenotype, problems in their differentiation and functional deficiencies that result in increased susceptibility to opportunistic infections. Among which, include changes in intracellular signaling, which results in altered production of specific cytokines, defects in phagocytosis and killing activity. However, little is known about the mechanisms that cause these defects in macrophages and whether or not epigenetic changes in immune system genes are involved in the dysfunction of macrophages. Thus, the objectives of this project are based on three fronts of investigation, through macrophages derived from HIV+ patients. We will study whether epigenetic changes induced in infection with HIV and HIV/tuberculosis co-infection are related to the regulation of macrophages innate immune response. In parallel, we will investigate how the classical and alternative activation of macrophages are involved in the pathways of inflammatory lipid mediator production after stimulation with bacterial and fungal PAMPs. This study will provide data for evaluation of aspects related to the pathogenesis and alternative therapies for opportunistic infections in AIDS. Finally, biomarkers will be searched for the innate immune response to the introduction of a new clinical parameter in determining the initiation of antiretroviral therapy (ART), since the parameter available in the clinic for initiation of therapy is the count of CD4+ T cells. Together, the overall data of this work can be important in prophylactic approaches, therapies and also for clinical diagnosis. (AU)