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Characterization of intracellular trafficking routes used by the HIV-1 Nef protein to downregulate Main Histocompatibility Complex (MHC) type I molecules.

Grant number: 12/19764-8
Support type:Scholarships in Brazil - Doctorate
Effective date (Start): January 01, 2013
Effective date (End): June 30, 2015
Field of knowledge:Biological Sciences - Morphology - Cytology and Cell Biology
Principal researcher:Luis Lamberti Pinto da Silva
Grantee:Julianne Vargas de Carvalho
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil


The HIV-1 developed several strategies to evade host innate and adaptive immune responses. Nef is an HIV-1 accessory protein involved evasion strategies that circumvent the immune system and play import roles in progression to AIDS. One of the functions ascribed to Nef is related to its capacity to downregulate the cell surface expression of MHC-I molecules in infected cells. This protects infected cell from being recognized and destroyed by cytotoxic T-cells. Nef alters the intracellular trafficking of MHC-I molecules, resulting in targeting of these proteins to lysosomes for degradation. Although this effect of Nef has been extensively documented little is know about the mechanisms by which Nef induces this changes in MHC-I targeting. Here we proposed to a combination of biochemical and microscopy approaches with the aim to identify intracellular trafficking routes and host cell factors involved in MHC-I downregulation by Nef. Specifically, we will test whether targeting of MHC-I to lysosomes by Nef requires the activity of the ESCRT (endosomal sorting complexes required for transport) machinery, as we have demonstrated previously for the effect of Nef on CD4. In addition, we will test if the induction of exocytosis, a recently identified function of Nef, contributes to the reduction of MHC-I expression on the cell surface. The better understanding of how Nef manipulates intracellular trafficking pathways could lead shed light on strategies to interfere with the activity of this remarkable viral protein.

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