| Autor: |
Galloway, Nicole Louise Katherine |
| Jazyk: |
angličtina |
| Rok vydání: |
2014 |
| Předmět: |
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| Zdroj: |
Galloway, Nicole Louise Katherine. (2014). Cell-to-cell transmission of HIV-1 is required to trigger pyroptotic death of CD4 T cells in lymphoid tissue. UC San Francisco: Biomedical Sciences. Retrieved from: http://www.escholarship.org/uc/item/1vk8r1mt |
| Popis: |
The pathway causing CD4 T-cell death in HIV-infected hosts remains poorly understood although apoptosis has been proposed as a key player. Our studies now show that caspase-3-mediated apoptosis only mediates the death of only a small fraction (95% of quiescent lymphoid CD4 T-cells die by caspase-1-mediated pyroptosis triggered as a result of abortive viral infection occurring in nonpermissive resting CD4 T cells. Pyroptosis is an intensely inflammatory form of programmed cell death where cytoplasmic contents and pro-inflammatory cytokines including IL-1β and IL-18 are released. This death pathway thus links the two signature events in HIV infection--CD4 T-cell depletion and chronic inflammation--in a single process and creates a vicious pathogenic cycle where dying CD4 T-cells release inflammatory signals that attract more cells to die. This cycle can be broken with caspase-1 inhibitors, including a compound already shown to be safe and well-tolerated in humans. These inhibitors could form a new class of "anti-AIDS" therapeutics that target the host rather than the virus. We further show that cell-to-cell transmission of HIV is obligately required for the induction of pyroptosis. Cell-free HIV-1 virions, even when added in large quantities, due not suffice. These findings underscore the infected CD4 T cell as the major killing unit promoting progression to AIDS and highlight a previously unappreciated biological role for the virological synapse. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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