CXCR4 tropic human immunodeficiency virus type 1 induces an apoptotic cascade in immature infected thymocytes that resembles thymocyte negative selection |
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Authors: | Choudhary Shailesh K Walker Russell M Powell Douglas M Planelles Vicente Walsh Craig Camerini David |
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Institution: | Department of Molecular Biology and Biochemistry, Center for Immunology and Center for Virus Research, University of California, Irvine, CA 92697-3900, USA. |
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Abstract: | HIV-1 often replicates in the thymus of infected individuals, causing thymocyte depletion and thymic dysfunction. Nevertheless, the mechanisms by which thymocyte depletion occurs are not clear. Here we report that HIV-1 infection induced apoptosis primarily in productively infected thymocytes; aldrithiol-2 or Efavirenz treatment largely abrogated HIV-1-induced apoptosis. Moreover, X4-HIV-1 induced apoptosis primarily in immature CD4+ CD8+ (DP) thymocytes whereas most mature CD4 or CD8 single-positive (SP) thymocytes were resistant to X4 HIV-1-induced apoptosis despite infection. Consistent with this, we observed significant induction of several genes involved in negative selection of DP thymocytes. Furthermore, treatment of thymocytes with cycloheximide abrogated HIV-1-induced apoptosis, implying a requirement for de novo protein synthesis. Our results suggest that HIV-1-induced apoptosis of thymocytes requires the activation of caspases and the participation of mitochondrial apoptosis effectors, which serve to amplify the apoptotic signal, a process similar to that elaborated during thymocyte negative selection. |
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Keywords: | HIV-1 Thymocyte Apoptosis Negative selection |
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