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Identification of novel cell surface proteins deferentially expressed in response to HIV-1 Nef in CD4+ t lymphocytes

Grant number: 11/18148-9
Support type:Scholarships in Brazil - Post-Doctorate
Effective date (Start): November 01, 2011
Effective date (End): August 31, 2014
Field of knowledge:Biological Sciences - Morphology
Principal Investigator:Luis Lamberti Pinto da Silva
Grantee:Rodrigo Orlandini de Castro
Home Institution: Faculdade de Medicina de Ribeirão Preto (FMRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Infection of human immunodeficiency virus, HIV-1, results in impaired function of the immune system that leads to clinical manifestations of AIDS. The genome of HIV-1 encodes nine proteins, among them is the accessory protein Nef. Although Nef lacks enzymatic activity, it has the capacity to change signaling pathways and to interfere with intracellular protein trafficking machinery, thereby modulating expression of specific proteins in the plasma membrane of host cells. The most characterized effect of Nef in T-cells is the reduction of expression of the co-receptor CD4 and MHC-I molecules on the cell surface. Interestingly, Nef has the capacity to modulate the expression of plasma membrane proteins via distinct mechanisms. Downregulation of CD4 occurs by binding of Nef to cytoplasmic tail of CD4 and the adapter protein AP-2. The protein complex formed by CD4/Nef/AP-2 recruits clathrin molecules and results in endocytosis which targets CD4 to multivesicular bodies. In case of MHC-I, Nef binds to the receptor and the adapter protein AP-1 in the trans-Golgi network, which impairs MHC-I transport to the cell surface. Other receptors such as CD28 and CD8-beta have also been identified as targets of Nef, but additional cell surface targets of Nef are likely to exist. Thus, the general aim of this project is to identify new proteins that are modulated by Nef, through a quantitative sub-proteomic approach, and to comparatively exam the role of the AP-1 and AP-2 complexes, as well as, the lysosomal activity in these processes. A comprehensive analysis of the changes in cell-surface protein composition induced by Nef and the identification of common requirements for the downregulation of its targets, will result in a better understanding of the role of Nef on the development of AIDS, and contribute to the identification of strategies to interfere with the actions of this viral protein.