学位论文详细信息
Intracellular Trafficking of MHC-I in Normal and HIV-1 Nef Expressing Cells.
HIV-1;MHC-I;CD4;Beta-COP;HLA-C;Intracellular Trafficking;Microbiology and Immunology;Health Sciences;Immunology
Schaefer, Malinda R.Raghavan, Malini ;
University of Michigan
关键词: HIV-1;    MHC-I;    CD4;    Beta-COP;    HLA-C;    Intracellular Trafficking;    Microbiology and Immunology;    Health Sciences;    Immunology;   
Others  :  https://deepblue.lib.umich.edu/bitstream/handle/2027.42/58478/mschaefe_1.pdf?sequence=1&isAllowed=y
瑞士|英语
来源: The Illinois Digital Environment for Access to Learning and Scholarship
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【 摘 要 】

HIV-1 establishes a chronic infection.To facilitate viral infection and spread, HIV-1 Nef disrupts the surface expression of the viral receptor (CD4) and antigen presenting molecules (MHC-I).Nef binds the cytoplasmic tails of both molecules and disrupts their trafficking using separate mechanisms that are incompletely understood.We demonstrate here that these distinct mechanisms are dictated by differences in the cytoplasmic tails of CD4 and MHC-I.Despite these differences, we demonstrate that MHC-I and CD4 are ultimately targeted to the same degradative compartments via interaction of Nef with the cellular protein -COP.Moreover, we demonstrate that the N-terminal -helical and dimerization domains of Nef are required for the Nef/-COP interaction.These findings have revealed the convergence of separate degradative pathways for CD4 and MHC-I, providing insight into the mechanisms used by HIV to evade the immune response.The removal of MHC-I from the cell surface protects HIV-infected cells from cytotoxic T lymphocytes.However, complete downmodulation of MHC-I by HIV Nef would render the infected cell susceptible to NK cell-mediated destruction.This scenario may be avoided by Nef’s inability to downmodulate certain MHC-I alleles, HLA-C and HLA-E, which inhibit NK cells.In the present work, we sought to better understand the biology of HLA-C in order to discern its role in HIV infection.Compared to other classical MHC-I allotypes, HLA-C has low cell surface expression and altered intracellular trafficking.Our studies have revealed that aspects of HLA-C trafficking are controlled by both the extracellular and cytosolic domains, in both CD4+ T cells and macrophages.Interestingly, we also found that HLA-C expression is upregulated upon macrophage differentiation, revealing the possibility of previously uncharacterized roles for HLA-C in the immune system.These studies bring us closer to understanding the role of HLA-C in the immune system and in HIV infection.The studies described in this thesis further our understanding of the interplay between HIV and the host immune system and provide insight into the biology of HLA-C in T cells and macrophages.Collectively, these data contribute significantly to our knowledge in areas crucial for the development of better antiretroviral therapies and vaccine strategies.

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