CARD8 is an Inflammasome Sensor for HIV-1 Protease Activity

Overview

Journal Science

Specialty Science

Date 2021 Feb 5

PMID 33542150

Citations 63

Authors

Qiankun Wang

Hongbo Gao

Kolin M Clark

Christian Shema Mugisha

Keanu Davis

Jack P Tang

Gray H Harlan

Carl J DeSelm

Rachel M Presti

Sebla B Kutluay

Liang Shan

Affiliations

Soon will be listed here.

Abstract

HIV-1 has high mutation rates and exists as mutant swarms within the host. Rapid evolution of HIV-1 allows the virus to outpace the host immune system, leading to viral persistence. Approaches to targeting immutable components are needed to clear HIV-1 infection. Here, we report that the caspase recruitment domain-containing protein 8 (CARD8) inflammasome senses HIV-1 protease activity. HIV-1 can evade CARD8 sensing because its protease remains inactive in infected cells before viral budding. Premature intracellular activation of the viral protease triggered CARD8 inflammasome-mediated pyroptosis of HIV-1-infected cells. This strategy led to the clearance of latent HIV-1 in patient CD4 T cells after viral reactivation. Thus, our study identifies CARD8 as an inflammasome sensor of HIV-1, which holds promise as a strategy for the clearance of persistent HIV-1 infection.

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References

Johnson D, Taabazuing C, Okondo M, Chui A, Rao S, Brown F . DPP8/DPP9 inhibitor-induced pyroptosis for treatment of acute myeloid leukemia. Nat Med. 2018; 24(8):1151-1156. PMC: 6082709. DOI: 10.1038/s41591-018-0082-y. View

Wong J, Hezareh M, Gunthard H, Havlir D, Ignacio C, Spina C . Recovery of replication-competent HIV despite prolonged suppression of plasma viremia. Science. 1997; 278(5341):1291-5. DOI: 10.1126/science.278.5341.1291. View

Mochizuki H, Schwartz J, Tanaka K, Brady R, Reiser J . High-titer human immunodeficiency virus type 1-based vector systems for gene delivery into nondividing cells. J Virol. 1998; 72(11):8873-83. PMC: 110304. DOI: 10.1128/JVI.72.11.8873-8883.1998. View

DOsualdo A, Weichenberger C, Wagner R, Godzik A, Wooley J, Reed J . CARD8 and NLRP1 undergo autoproteolytic processing through a ZU5-like domain. PLoS One. 2011; 6(11):e27396. PMC: 3210808. DOI: 10.1371/journal.pone.0027396. View

Linder A, Bauernfried S, Cheng Y, Albanese M, Jung C, Keppler O . CARD8 inflammasome activation triggers pyroptosis in human T cells. EMBO J. 2020; 39(19):e105071. PMC: 7527815. DOI: 10.15252/embj.2020105071. View

Trinite B, Zhang H, Levy D . NNRTI-induced HIV-1 protease-mediated cytotoxicity induces rapid death of CD4 T cells during productive infection and latency reversal. Retrovirology. 2019; 16(1):17. PMC: 6595680. DOI: 10.1186/s12977-019-0479-9. View

Park J, Morrow C . Overexpression of the gag-pol precursor from human immunodeficiency virus type 1 proviral genomes results in efficient proteolytic processing in the absence of virion production. J Virol. 1991; 65(9):5111-7. PMC: 248980. DOI: 10.1128/JVI.65.9.5111-5117.1991. View

Finzi D, Hermankova M, Pierson T, Carruth L, Buck C, Chaisson R . Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy. Science. 1997; 278(5341):1295-300. DOI: 10.1126/science.278.5341.1295. View

Ganor Y, Real F, Sennepin A, Dutertre C, Prevedel L, Xu L . HIV-1 reservoirs in urethral macrophages of patients under suppressive antiretroviral therapy. Nat Microbiol. 2019; 4(4):633-644. DOI: 10.1038/s41564-018-0335-z. View

10.

Wei X, Decker J, Wang S, Hui H, Kappes J, Wu X . Antibody neutralization and escape by HIV-1. Nature. 2003; 422(6929):307-12. DOI: 10.1038/nature01470. View

11.

Bauernfried S, Scherr M, Pichlmair A, Duderstadt K, Hornung V . Human NLRP1 is a sensor for double-stranded RNA. Science. 2020; 371(6528). DOI: 10.1126/science.abd0811. View

12.

Chun T, Stuyver L, Mizell S, Ehler L, Mican J, Baseler M . Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A. 1997; 94(24):13193-7. PMC: 24285. DOI: 10.1073/pnas.94.24.13193. View

13.

Fagerberg L, Hallstrom B, Oksvold P, Kampf C, Djureinovic D, Odeberg J . Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics. Mol Cell Proteomics. 2013; 13(2):397-406. PMC: 3916642. DOI: 10.1074/mcp.M113.035600. View

14.

Ball D, Taabazuing C, Griswold A, Orth E, Rao S, Kotliar I . Caspase-1 interdomain linker cleavage is required for pyroptosis. Life Sci Alliance. 2020; 3(3). PMC: 7025033. DOI: 10.26508/lsa.202000664. View

15.

Johnson D, Okondo M, Orth E, Rao S, Huang H, Ball D . DPP8/9 inhibitors activate the CARD8 inflammasome in resting lymphocytes. Cell Death Dis. 2020; 11(8):628. PMC: 7428001. DOI: 10.1038/s41419-020-02865-4. View

16.

Caskey M, Klein F, Lorenzi J, Seaman M, West Jr A, Buckley N . Viraemia suppressed in HIV-1-infected humans by broadly neutralizing antibody 3BNC117. Nature. 2015; 522(7557):487-91. PMC: 4890714. DOI: 10.1038/nature14411. View

17.

Scheid J, Horwitz J, Bar-On Y, Kreider E, Lu C, Lorenzi J . HIV-1 antibody 3BNC117 suppresses viral rebound in humans during treatment interruption. Nature. 2016; 535(7613):556-60. PMC: 5034582. DOI: 10.1038/nature18929. View

18.

Kwong P, Doyle M, Casper D, Cicala C, Leavitt S, Majeed S . HIV-1 evades antibody-mediated neutralization through conformational masking of receptor-binding sites. Nature. 2002; 420(6916):678-82. DOI: 10.1038/nature01188. View

19.

Chavarria-Smith J, Vance R . The NLRP1 inflammasomes. Immunol Rev. 2015; 265(1):22-34. DOI: 10.1111/imr.12283. View

20.

Siliciano J, Siliciano R . Enhanced culture assay for detection and quantitation of latently infected, resting CD4+ T-cells carrying replication-competent virus in HIV-1-infected individuals. Methods Mol Biol. 2005; 304:3-15. DOI: 10.1385/1-59259-907-9:003. View