Prime, Shock, and Kill: Priming CD4 T Cells from HIV Patients with a BCL-2 Antagonist before HIV Reactivation Reduces HIV Reservoir Size
| Autor: | Rahul Sampath, Sekar Natesampillai, Yuan Ping Pang, Gary D. Bren, Amy M. Sainski, Nathan W. Cummins, Haiming Dai, Joseph D. Yao, Scott H. Kaufmann, Andrew D. Badley, Daniel R. O'Brien, Stacey A. Rizza, Maria Cristina Miranda De Araujo Correia |
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| Rok vydání: | 2015 |
| Předmět: |
0301 basic medicine
CD4-Positive T-Lymphocytes Chemokine receptor CCR5 Immunology Priming (immunology) Apoptosis HIV Infections Microbiology Jurkat cells 03 medical and health sciences chemistry.chemical_compound Jurkat Cells 0302 clinical medicine Virology Humans Caspase 8 Sulfonamides biology Cell Death Venetoclax HEK 293 cells virus diseases Viral Load Bridged Bicyclo Compounds Heterocyclic Caspase Inhibitors Peptide Fragments Virus-Cell Interactions 030104 developmental biology HEK293 Cells bcl-2 Homologous Antagonist-Killer Protein chemistry 030220 oncology & carcinogenesis Insect Science biology.protein HIV-1 Virus Activation Viral load Immunologic Memory Bcl-2 Homologous Antagonist-Killer Protein Protein Binding |
| Zdroj: | Journal of virology. 90(8) |
| ISSN: | 1098-5514 |
| Popis: | Understanding how some HIV-infected cells resist the cytotoxicity of HIV replication is crucial to enabling HIV cure efforts. HIV killing of CD4 T cells that replicate HIV can involve HIV protease-mediated cleavage of procaspase 8 to generate a fragment (Casp8p41) that directly binds and activates the mitochondrial proapoptotic protein BAK. Here, we demonstrate that Casp8p41 also binds with nanomolar affinity to the antiapoptotic protein Bcl-2, which sequesters Casp8p41 and prevents apoptosis. Further, we show that central memory CD4 T cells (T CM ) from HIV-infected individuals have heightened expression of BCL-2 relative to procaspase 8, possibly explaining the persistence of HIV-infected T CM despite generation of Casp8p41. Consistent with this hypothesis, the selective BCL-2 antagonist venetoclax induced minimal killing of uninfected CD4 T cells but markedly increased the death of CD4 T cells and diminished cell-associated HIV DNA when CD4 T cells from antiretroviral therapy (ART)-suppressed HIV patients were induced with αCD3/αCD28 to reactivate HIV ex vivo . Thus, priming CD4 T cells from ART suppressed HIV patients with a BCL-2 antagonist, followed by HIV reactivation, achieves reductions in cell-associated HIV DNA, whereas HIV reactivation alone does not. IMPORTANCE HIV infection is incurable due to a long-lived reservoir of HIV + memory CD4 T cells, and no clinically relevant interventions have been identified that reduce the number of these HIV DNA-containing cells. Since postintegration HIV replication can result in HIV protease generation of Casp8p41, which activates BAK, causing infected CD4 T cell death, we sought to determine whether this occurs in memory CD4 T cells. Here, we demonstrate that memory CD4 T cells can generate Casp8p41 and yet are intrinsically resistant to death induced by diverse stimuli, including Casp8p41. Furthermore, BCL-2 expression is relatively increased in these cells and directly binds and inhibits Casp8p41's proapoptotic effects. Antagonizing BCL-2 with venetoclax derepresses this antagonism, resulting in death, preferentially in HIV DNA containing cells, since only these cells generate Casp8p41. Thus, BCL-2 antagonism is a clinically relevant intervention with the potential to reduce HIV reservoir size in patients. |
| Databáze: | OpenAIRE |
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