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; 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.
Choudhary
Shailesh K
SK
Department of Molecular Biology and Biochemistry, Center for Immunology and Center for Virus Research, University of California, Irvine, CA 92697-3900, USA.
Walker
Russell M
RM
Powell
Douglas M
DM
Planelles
Vicente
V
Walsh
Craig
C
Camerini
David
D
D017209:Apoptosis / Q000235:genetics / Q000276:immunology / Q000502:physiology; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D002454:Cell Differentiation; D016572:Cyclosporine / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D015870:Gene Expression; D015658:HIV Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000821:virology; D015497:HIV-1 / Q000472:pathogenicity* / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D014176:Protein Biosynthesis; D019718:Receptors, CXCR4 / Q000502:physiology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology / Q000821:virology*; D014779:Virus Replication
D015704:CD4 Antigens; D016827:CD8 Antigens; D005419:Flavonoids; D019718:Receptors, CXCR4; D016572:Cyclosporine; D020169:Caspases; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one