The Human Immunodeficiency Virus type 1 (HIV-1) is the main retroviral agent responsible for the infection and progression to Acquired Immunodeficiency Syndrome (AIDS). There is no cure for HIV-1 infection, nevertheless, the implementation of antiviral therapies allowed to reduce the mortality rates and enhance the life expectancy of infected individuals. The HIV-1 encodes structural proteins common to all retrovirus and specific accessories proteins. Nef is an abundantly express accessory protein in the early stages of infection. The Nef enhances viral pathogenicity through modification of intracellular trafficking and localization of plasma membrane proteins plasmatic with roles in the immune response. The most studied targets of Nef are the CD4 receptor and MHC class I molecules (MHC-I). After infection, Nef decreases the expression of CD4, the main HIV receptor, to facilitate viral progeny budding and to avoid superinfection of virus producer cells. The down regulation of MHC-I by Nef prevents viral antigen presentation to cytotoxic T lymphocytes, which sustains the HIV infection. The IFN-1 are cytokines that are synthesized and released during viral infections and can promote inflammatory responses through the activation of the signaling JAK/STAT pathway. Activation of this pathway triggers the transcription of ISGs that encode antiviral factors, some of which with documented activity against HIV (such as APOBEC3G, Tetherin, and IFITMs). Recent findings in the literature and results from our research group revealed that Nef acts inhibiting the STAT1 phosphorylation and blocking the JAK/STAT pathway, through a yet unknown mechanism. In this project, we propose to investigate a possible Nef-mediated interference with IFNAR intracellular trafficking as a form of inhibiting the activation of the JAK/STAT signaling pathway.
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