Casp8p41 expression in primary T cells induces a proinflammatory response.

Abstract

OBJECTIVE:

HIV infection of CD4 T cells can lead to HIV protease-mediated cleavage of procaspase 8 generating a novel, HIV-specific peptide called Casp8p41. Casp8p41 has at least two biologic functions: induction of cell death via mitochondrial depolarization and release of cytochrome C, as well as activation of nuclear factor kappa B (NFkappaB). We have previously shown that Casp8p41-induced NFkappaB activation enhances HIV LTR transcription and consequently increases HIV replication. Herein, we questioned whether Casp8p41-induced NFkappaB activation impacts the cytokine profile of cells expressing Casp8p41.

DESIGN:

Analysis of cells expressing Casp8p41 and HIV-infected T cells.

METHODS:

We assessed whether host genes are transcriptionally activated following Casp8p41 production, using microarray analysis, cytokine quantification, followed by western blot and flow cytometry.

RESULTS:

Microarray analysis identified 259 genes significantly upregulated following expression of Casp8p41. Furthermore, Casp8p41 expression in primary CD4 T cells results in increased production of interleukin (IL)-2, IL-15 and tumor necrosis factor (TNF), as well as IL-1RA; whereas levels of granulocyte macrophage colony-stimulating factor and interferon (IFN)-gamma were reduced in the Casp8p41 expressing cells. Intracellular flow cytometry confirmed the co-association of Casp8p41 with elevated TNF in HIV-infected cells.

CONCLUSION:

These data indicate that the expression of Casp8p41 in HIV-infected CD4 T cells in addition to promoting apoptosis and enhancing HIV replication also promotes a proinflammatory cytokine milieu, which is characteristic of untreated HIV infection.

• Authors: Julie A Taylor, Nathan W Cummins, Gary D Bren, Stacey A Rizza, Christopher P Kolbert, Marshall D Behrens, Keith L Knutson, Jane C Kahl, Yan W Asmann, Andrew D Badley
• Journal: AIDS (London, England) (AIDS) Vol. 24 Issue 9 Pg. 1251-8 (Jun 01 2010) ISSN: 1473-5571 [Electronic] England
• PMID: 20299954 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Cytokines
• Interleukin-15
• Interleukin-2
• Interleukin-2 Receptor alpha Subunit
• NF-kappa B
• CASP8 protein, human
• Caspase 8

Topics

• Blotting, Western
• CD4-Positive T-Lymphocytes (enzymology, metabolism)
• Caspase 8 (genetics, metabolism)
• Cytokines (biosynthesis)
• HIV Infections (immunology, virology)
• HIV-1 (physiology)
• Humans
• Interleukin-15 (biosynthesis)
• Interleukin-2 (biosynthesis)
• Interleukin-2 Receptor alpha Subunit (biosynthesis)
• Lymphocyte Activation
• NF-kappa B (biosynthesis)
• Virus Replication (physiology)