CXCR4 tropic human immunodeficiency virus type 1 induces an apoptotic cascade in immature infected thymocytes that resembles thymocyte negative selection

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; aldri...

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Bibliographic Details
Published in:Virology (New York, N.Y.) N.Y.), 2006-09, Vol.352 (2), p.268-284
Main Authors: Choudhary, Shailesh K., Walker, Russell M., Powell, Douglas M., Planelles, Vicente, Walsh, Craig, Camerini, David
Format: Article
Language:English
Subjects:
Apoptosis
Apoptosis - genetics
Apoptosis - immunology
Apoptosis - physiology
Caspases - metabolism
CD4 Antigens - metabolism
CD8 Antigens - metabolism
Cell Differentiation
Cyclosporine - pharmacology
Flavonoids - pharmacology
Gene Expression
HIV Infections - genetics
HIV Infections - immunology
HIV Infections - pathology
HIV Infections - virology
HIV-1
HIV-1 - pathogenicity
HIV-1 - physiology
Human immunodeficiency virus 1
Humans
In Vitro Techniques
Negative selection
Protein Biosynthesis
Receptors, CXCR4 - physiology
T-Lymphocytes - drug effects
T-Lymphocytes - immunology
T-Lymphocytes - pathology
T-Lymphocytes - virology
Thymocyte
Virus Replication
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Summary: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.
ISSN:0042-6822
1096-0341
DOI:10.1016/j.virol.2006.04.037