ABSTRACT
Interleukin 1ß is a pro-inflammatory cytokine important for both normal immune responses and chronic inflammatory diseases. The regulation of the 31â¯kDa proIL-1ß precursor coded by the IL1B gene has been extensively studied in myeloid cells, but not in lymphoid-derived CD4 T cells. Surprisingly, we found that some CD4 T cell subsets express higher levels of proIL-1ß than unstimulated monocytes, despite relatively low IL1B mRNA levels. We observed a significant increase in IL1B transcription and translation in CD4 T cells upon ex vivo CD3/CD28 activation, and a similar elevation in the CCR5+ effector memory population compared to CCR5- T cells in vivo. The rapid and vigorous increase in IL1B gene transcription for stimulated monocytes has previously been associated with the presence of Spi-1/PU.1 (Spi1), a myeloid-lineage transcription factor, pre-bound to the promoter. In the case of CD4 T cells, this increase occurred despite the lack of detectable Spi1 at the IL1B promoter. Additionally, we found altered epigenetic regulation of the IL1B locus in CD3/CD28-activated CD4 T cells. Unlike monocytes, activated CD4 T cells possess bivalent H3K4me3+/H3K27me3+ nucleosome marks at the IL1B promoter, reflecting low transcriptional activity. These results support a model in which the IL1B gene in CD4 T cells is transcribed from a low-activity bivalent promoter independent of Spi1. Accumulated cytoplasmic proIL-1ß may ultimately be cleaved to mature 17â¯kDa bioactive IL-1ß, regulating T cell polarization and pathogenic chronic inflammation.
Subject(s)
CD4-Positive T-Lymphocytes/physiology , Interleukin-1beta/genetics , Monocytes/physiology , Transcription, Genetic/genetics , Biomarkers/metabolism , CD28 Antigens/genetics , CD3 Complex/genetics , Epigenesis, Genetic/genetics , Gene Expression Regulation/genetics , Humans , Nucleosomes/genetics , Promoter Regions, Genetic/genetics , Proto-Oncogene Proteins/genetics , RNA, Messenger/genetics , Receptors, CCR5/genetics , Transcriptional Activation/geneticsABSTRACT
The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood although apoptosis has been proposed as a key mechanism. We now show that caspase-3-mediated apoptosis accounts for the death of only a small fraction of CD4 T cells corresponding to those that are both activated and productively infected. The remaining over 95% of quiescent lymphoid CD4 T cells die by caspase-1-mediated pyroptosis triggered by abortive viral infection. Pyroptosis corresponds to an intensely inflammatory form of programmed cell death in which cytoplasmic contents and pro-inflammatory cytokines, including IL-1ß, are released. This death pathway thus links the two signature events in HIV infection-CD4 T-cell depletion and chronic inflammation-and creates a pathogenic vicious cycle in which dying CD4 T cells release inflammatory signals that attract more cells to die. This cycle can be broken by caspase 1 inhibitors shown to be safe in humans, raising the possibility of a new class of 'anti-AIDS' therapeutics targeting the host rather than the virus.
Subject(s)
CD4-Positive T-Lymphocytes/pathology , Caspase 1/metabolism , HIV Infections/immunology , HIV Infections/pathology , HIV-1/pathogenicity , Administration, Oral , Adult , Anti-HIV Agents/pharmacology , CD4-Positive T-Lymphocytes/cytology , CD4-Positive T-Lymphocytes/drug effects , CD4-Positive T-Lymphocytes/metabolism , Caspase 3/metabolism , Caspase Inhibitors/administration & dosage , Caspase Inhibitors/pharmacology , Cell Death/drug effects , HIV Infections/drug therapy , HIV Infections/enzymology , HIV-1/drug effects , HIV-1/growth & development , Humans , In Vitro Techniques , Inflammasomes/immunology , Inflammasomes/metabolism , Inflammation/complications , Inflammation/immunology , Inflammation/pathology , Inflammation/virology , Interleukin-1beta/biosynthesis , Interleukin-1beta/metabolism , Lymph Nodes/enzymology , Male , Palatine Tonsil/drug effects , Palatine Tonsil/virology , Protein Precursors/biosynthesis , Spleen/drug effects , Spleen/virology , Virus ReplicationABSTRACT
The Vif protein of HIV is essential for the effective propagation of this pathogenic retrovirus in vivo. Vif acts by preventing virion encapsidation of two potent antiviral factors, the APOBEC3G and APOBEC3F cytidine deaminases. Decreased encapsidation in part involves Vif-mediated recruitment of a ubiquitin E3 ligase complex that promotes polyubiquitylation and proteasome-mediated degradation of APOBEC3G/F. The resultant decline in intracellular levels of these enzymes leads to decreased encapsidation of APOBECG/F into budding virions. This review discusses recent advances in our understanding of the dynamic interplay of Vif with the antiviral APOBEC3 enzymes.