Chemical inhibition of DPP9 sensitizes the CARD8 inflammasome in HIV-1-infected cells

Clark, Kolin M.; Kim, Josh G; Wang, Qiankun; Gao, Hongbo; Presti, Rachel; Shan, Liang

doi:10.1038/s41589-022-01182-5

Cited by 19 publications

(21 citation statements)

References 43 publications

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“…Dipeptidyl peptidase 9 (DPP9) negatively regulates CARD8 activity by binding to and sequestrating the bioactive CARD8 C-fragment 22 . Thus, abolishing CARD8 and DPP9 interaction sensitizes the CARD8 inflammasome in cells exposed to HIV-1 particles 23 . While the DPP9 inhibitor 1G244 alone at ≤1μM did not drive cell death, it greatly enhanced HIV-1 entry triggered pyroptosis of CD4 + T cells ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…HEK 293T cells (ATCC #CRL-3216) and ACH-2 cells (AIDS Reagent Program #349) were cultured in DMEM or RPMI containing 10% heat-inactivated fetal bovine serum (FBS), 1 U/ml penicillin, and 100□mg/ml streptomycin (Gibco). THP-1 cells carrying doxycycline-inducible CARD8 expression cassettes were described previously 23 and cultured in RPMI 1640 medium supplemented with 10% FBS, 1 U/ml penicillin, and 100Cmg/ml streptomycin. Blood or tonsil CD4 + T cells were isolated using a human CD4 + T cell isolation kit (BioLegend #480010).…”

Section: Methodsmentioning

confidence: 99%

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The CARD8 inflammasome drives CD4⁺T-cell depletion in HIV-1 infection

Wang

Shan

2023

Preprint

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CD4+ T-cell depletion is the root cause of acquired immunodeficiency syndrome (AIDS). How HIV depletes CD4+ T cells in humans remains unknown because vast majority of the dying CD4+ T cells in patients are uninfected. Burgeoning evidence supports the hypothesis that non-productive HIV-1 infection triggers CD4+ T-cell depletion in the course of pathogenic HIV and SIV infections. Here, we report that the CARD8 inflammasome is activated immediately after HIV-1 entry by the viral protease encapsulated in the incoming HIV-1 particles. Sensing of HIV-1 protease activity by the CARD8 inflammasome leads to rapid pyroptosis of quiescent CD4+ T cells without productive viral infection. T cell activation abolishes the CARD8 function and increases the host permissiveness to HIV-1 infection. In humanized mice reconstituted with a CARD8-deficient immune system, CD4+ T-cell loss is delayed despite increased levels of HIV-1 replication. Our study suggests that the CARD8 inflammasome drives CD4+ T-cell depletion and disease progression through rapid sensing of HIV-1 particles.

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Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

The CARD8 inflammasome drives CD4⁺T-cell depletion in HIV-1 infection

Wang

Shan

2023

Preprint

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“…DPP9 inhibitors such as Vbp bind to the DPP9-CARD8 heterodimer and prevent heterotrimer formation, leading to increased intracellular concentrations of the C-terminal fragment [64]. Clark et al showed that Vbp acts synergistically with NNRTIs lowering the threshold for protease activity and Gag-pol dimerization needed to induce CARD8 activation in infected cells [66 ▪ ]. It is important to note that this strategy is currently not easy to implement.…”

Section: The Card8 Inflammasome and Pyroptosismentioning

confidence: 99%

Pharmacological approaches to promote cell death of latent HIV reservoirs

Pinzone,

Shan

2023

Current Opinion in HIV and AIDS

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Purpose of review HIV requires lifelong antiviral treatment due to the persistence of a reservoir of latently infected cells. Multiple strategies have been pursued to promote the death of infected cells. Recent findings Several groups have focused on multipronged approaches to induce apoptosis of infected cells. One approach is to combine latency reversal agents with proapoptotic compounds and cytotoxic T cells to first reactivate and then clear infected cells. Other strategies include using natural killer cells or chimeric antigen receptor cells to decrease the size of the reservoir. A novel strategy is to promote cell death by pyroptosis. This mechanism relies on the activation of the caspase recruitment domain-containing protein 8 (CARD8) inflammasome by the HIV protease and can be potentiated by nonnucleoside reverse transcriptase inhibitors. Summary The achievement of a clinically significant reduction in the size of the reservoir will likely require a combination strategy since none of the approaches pursued so far has been successful on its own in clinical trials. This discrepancy between promising in vitro findings and modest in vivo results highlights the hurdles of identifying a universally effective strategy given the wide heterogeneity of the HIV reservoirs in terms of tissue location, capability to undergo latency reversal and susceptibility to cell death.

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“…Moreover, X-ray crystallography indeed demonstrates that the tertiary and quaternary structures of DPP8 and DPP9 are largely superimposable . Nonetheless, more recent research involving knockout cell lines, CRISPR Cas9 experiments, and enzymatically inactive DPP9 mutants strongly points in the direction of DPP9 and not DPP8 as the main player in pyroptosis. , …”

Section: Introductionmentioning

confidence: 98%

“…Seminal reports by Bachovchin and co-workers focused on acute myeloid leukemia (AML) cell lines and primary AML cells . DPP9-dependent, pyroptosis-like pathways have meanwhile also been identified in other human cell types like primary human resting T cells, keratinocytes, and HIV-infected peripheral blood mononuclear cells and HIV-infected CD4+-T lymphocytes . Bachovchin and co-workers were also the first to successfully use the pan-DPP inhibitor Val -boro Pro (VbP or Talabostat) in a murine model of AML and to demonstrate selective pyroptosis induction of AML cells in vivo .…”

Section: Introductionmentioning

confidence: 99%

Highly Selective Inhibitors of Dipeptidyl Peptidase 9 (DPP9) Derived from the Clinically Used DPP4-Inhibitor Vildagliptin

Benramdane,

De Loose,

Filippi

et al. 2023

J. Med. Chem.

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Dipeptidyl peptidase 9 (DPP9) is a proline-selective serine protease that plays a key role in NLRP1-and CARD8-mediated inflammatory cell death (pyroptosis). No selective inhibitors have hitherto been reported for the enzyme: all published molecules have grossly comparable affinities for DPP8 and 9 because of the highly similar architecture of these enzymes' active sites. Selective DPP9 inhibitors would be highly instrumental to address unanswered research questions on the enzyme's role in pyroptosis, and they could also be investigated as therapeutics for acute myeloid leukemias. Compounds presented in this manuscript (42 and 47) combine low nanomolar DPP9 affinities with unprecedented DPP9-to-DPP8 selectivity indices up to 175 and selectivity indices >1000 toward all other proline-selective proteases. To rationalize experimentally obtained data, a molecular dynamics study was performed. We also provide in vivo pharmacokinetics data for compound 42.

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Chemical inhibition of DPP9 sensitizes the CARD8 inflammasome in HIV-1-infected cells

Cited by 19 publications

References 43 publications

The CARD8 inflammasome drives CD4⁺T-cell depletion in HIV-1 infection

The CARD8 inflammasome drives CD4⁺T-cell depletion in HIV-1 infection

Pharmacological approaches to promote cell death of latent HIV reservoirs

Highly Selective Inhibitors of Dipeptidyl Peptidase 9 (DPP9) Derived from the Clinically Used DPP4-Inhibitor Vildagliptin

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Chemical inhibition of DPP9 sensitizes the CARD8 inflammasome in HIV-1-infected cells

Cited by 19 publications

References 43 publications

The CARD8 inflammasome drives CD4+T-cell depletion in HIV-1 infection

The CARD8 inflammasome drives CD4+T-cell depletion in HIV-1 infection

Pharmacological approaches to promote cell death of latent HIV reservoirs

Highly Selective Inhibitors of Dipeptidyl Peptidase 9 (DPP9) Derived from the Clinically Used DPP4-Inhibitor Vildagliptin

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The CARD8 inflammasome drives CD4⁺T-cell depletion in HIV-1 infection

The CARD8 inflammasome drives CD4⁺T-cell depletion in HIV-1 infection