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 (NFκB). We have previously shown that Casp8p41-induced NFκB activation enhances HIV LTR transcription and consequently increases HIV replication. Herein, we questioned whether Casp8p41-induced NFκB 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)-γ 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.
aDivision of Infectious Diseases, USA
bAdvanced Genomic Technology Center, USA
cDivision of Immunology, USA
dBiomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota, USA.
Received 9 November, 2009
Revised 3 February, 2010
Accepted 10 February, 2010
Correspondence to Andrew D. Badley, MD, Mayo Clinic, 200 First Street SW, Guggenheim 501, Rochester, MN 55905, USA. Tel: +1 507 284 2028; fax: +1 507 284 3757; e-mail: firstname.lastname@example.org