A human-specific motif facilitates CARD8 inflammasome activation after HIV-1 infection

  1. Jessie Kulsuptrakul
  2. Elizabeth A Turcotte
  3. Michael Emerman
  4. Patrick S Mitchell

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    The study shows that human inflammasome-forming sensor CARD8 contains a specific motif that allows cleavage by the proteases of HIV-1 and its direct precursor infecting chimpanzees. In comparison, CARD8 proteins from non-human primates contain changes in this motif and seem largely resistant to proteolytic activation. The results are important, and the data on the cleavage of CARD8 in HEK293T cells are convincing, while effects on inflammasome stimulation and cell death in primary viral target cells are insufficiently supported.

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Abstract

Inflammasomes are cytosolic innate immune complexes that assemble upon detection of diverse pathogen-associated cues and play a critical role in host defense and inflammatory pathogenesis. Here, we find that the human inflammasome-forming sensor CARD8 senses HIV-1 infection via site-specific cleavage of the CARD8 N-terminus by the HIV protease (HIV-1 PR ). HIV-1 PR cleavage of CARD8 induces pyroptotic cell death and the release of pro-inflammatory cytokines from infected cells, processes regulated by Toll-like receptor stimulation prior to viral infection. In acutely infected cells, CARD8 senses the activity of both de novo translated HIV-1 PR and packaged HIV-1 PR that is released from the incoming virion. Moreover, our evolutionary analyses reveal that the HIV-1 PR cleavage site in human CARD8 arose after the divergence of chimpanzees and humans. Although chimpanzee CARD8 does not recognize proteases from HIV or simian immunodeficiency viruses from chimpanzees (SIVcpz), SIVcpz does cleave human CARD8, suggesting that SIVcpz was poised to activate the human CARD8 inflammasome prior to its cross-species transmission into humans. Our findings suggest a unique role for CARD8 inflammasome activation in response to lentiviral infection of humans.

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  1. Version published to 10.7554/elife.84108 on eLife
  2. eLife

    Author Response

    Reviewer #1 (Public Review):

    It has recently been shown that the HIV-1 protease can cleave and activate the inflammasome-forming sensor CARD8 upon treatment of infected cells with non-nucleoside reverse-transcriptase inhibitors (Wang et al., Science 2021). Here, Kulsuptrakul and colleagues show that the high susceptibility to proteolytic activation by the HIV-1 protease is a specific feature of human CARD8. They show that changes in human-specific F-F motif render the CARD8 protein of non-human primates largely resistant to cleavage. Interestingly, the protease of SIVcpz the direct precursor of pandemic HIV-1 strains are also capable of cleaving human but not chimpanzee CARD8. Thus, the authors propose that a human-specific CARD8 motif may contribute to the increased levels of inflammation and disease progression in HIV-infected humans compared to non-human primates that are naturally infected with SIV.

    Strengths of the study are that the authors convincingly show that a single human-specific amino acid change in CARD8 determines its susceptibility to cleavage by the HIV-1 protease and that the results shown are well controlled and presented. It is also interesting that SIVcpz can cleave human CARD8 and activate an inflammatory response. The major weakness is that it remains unclear whether HIV-1 of SIVcpz may induce CARD8-dependent inflammatory responses in primary CD4+ T cells or macrophages. The most relevant setting in the study was the infection of THP-1 cells with the T cell line-adapted X4-tropic HIV-1 LAI molecular clone. However, the effects on cell death were modest (Figure 3A) and on IL-1ß secretion was not dose-dependent (Figure 3B). Altogether, stronger effects were observed with VSV-G-pseudotyped HIV-1 and only those were used in subsequent experiments involving human CARD8 cleavage mutants (Figure 4). Additional evidence that primary HIV-1 molecular clones and/or SIVcpz may indeed induce CARD8-dependent inflammatory responses in primary viral target cells would greatly increase the significance of the study. In the absence of such data, conclusions about the potential role of CARD8 sensing of the viral protease for the pathogenesis of AIDS should be cautioned throughout.

    We have now added an experiment using the HIV-1 strain BG505, which uses a distinct co-receptor and is from a different clade than LAI. The results show that BG505 infection also induces CARD8-depdenent inflammasome activation (Figure 3E).

    We have also more specifically measured caspase-1 activation using a FLICA assay (which specifically measures active CASP1) in WT, CARD8 KO and CASP1 KO THP-1 cells (Figure 3D, right panel). In experiments with both VSV-g pseudotyped and infectious virus, we observed increased FLICA signal in WT but not CASP1 KO THP-1 cells. Moreover, the FLICA signal and other readouts of inflammasome activation in CARD8 KO THP-1 cells was indistinguishable from the CASP1 KO THP-1 cells (Figure 3D). Thus, our results are consistent with HIV-1 infection inducing CASP1-dependent pyroptosis downstream of CARD8.

    While we agree with the reviewers that primary cell data would be informative, we believe that this is not the main point of our paper. Moreover, others have already shown CARD8-dependent cell death after infection of primary T cells with HIV-1 (Wang et al., 2021, Science; Clark et al. 2022, Nature Chem Biol; Balibar et al. 2023, Science Trans Med; Wang & Shan, 2023, BioRxiv). We therefore have not extensively pursued primary cell experiments in this manuscript and instead have elected to use a more easily manipulatable cell line to focus on the evolutionary and mechanistic basis of CARD8 activation by simian lentiviruses.

  3. PREreview

    This Zenodo record is a permanently preserved version of a PREreview. You can view the complete PREreview at https://prereview.org/reviews/8033242.

    We, the students of MICI5029/5049, a Graduate Level Molecular Pathogenesis Journal Club at Dalhousie University in Halifax, NS, Canada, hereby submit a review of the following BioRxiv preprint: 

    A human-specific motif facilitates CARD8 inflammasome activation after HIV-1 infection  

    Jessie Kulsuptrakul, Elizabeth A. Turcotte, Michael Emerman* and Patrick S. Mitchell* doi: https://doi.org/10.1101/2022.10.04.510817

    We will adhere to the Universal Principled (UP) Review guidelines proposed in: 

    Universal Principled Review: A Community-Driven Method to Improve Peer Review. Krummel M, Blish C, Kuhns M, Cadwell K, Oberst A, Goldrath A, Ansel KM, Chi H, O'Connell R, Wherry EJ, Pepper M; Future Immunology Consortium. Cell. 2019 Dec 12;179(7):1441-1445. doi: 10.1016/j.cell.2019.11.029 

    SUMMARY: CARD8 is thought to sense infection stress and stimulate inflammasome formation, but precise mechanisms remain to be elucidated. HIV-1 protease (HIV-1PR) cleaves CARD8, resulting in proteasome-dependent degradation of the amino-terminal CARD8 fragment and liberation of the carboxy-terminal fragment that activates inflammasomes. Kulsuptrakul and colleagues build upon this intriguing finding to investigate evolutionary relationships between primate lentiviruses and CARD8 homologs from their host primates. They discovered that both HIV-1 and SIVcpzproteases cleave human CARD8. By contrast, chimpanzee CARD8 was not cleaved by primate lentivirus proteases. Thus, even prior to the HIV-1 pandemic, SIVcpz proteases could cleave and activate human CARD8. The authors provided evidence for CARD8-dependent inflammasome activation in an in vitro HIV-1 infection model. Complementation of CARD8 KO cells with WT human CARD8 restored inflammasome activation, whereas complementation with chimpanzee CARD8 or human CARD8 mutant constructs with substitutions that destroy the protease cleavage site did not. Together, these findings support a role for human CARD8 in activating the inflammasome upon HIV infection and suggest that, during spillover events, SIVcpz was well equipped to cleave human CARD8 and drive pathogenesis.

    OVERALL ASSESSMENT: This study convincingly demonstrates that human CARD8 is susceptible to cleavage and activation by diverse primate lentivirus protease enzymes, whereas chimpanzee CARD8 is not. Overall, the data is quite convincing and clearly organized and rendered for readers, and positions lentivirus proteases and host CARD8 sensors as new players in the 'genomes-in-conflict' chess match. These conclusions could be strengthened by additional evidence for CARD8-mediated inflammasome activation.  

    STRENGTHS: The manuscript is well-written. The rationale provided for the investigation of CARD8 in the context of HIV infection is sound. The data presented is well-organized, clear and well-controlled. The primary strength is the identification and careful mapping of viral protease-mediated cleavage and activation of human CARD8, whereas the closely related chimpanzee CARD8 resists cleavage and activation.  

    WEAKNESSES: While the manuscript was well written, the introduction was quite brief. We suggest that the authors should provide some additional information about CARD8 and inflammasomes. Does CARD8 have additional roles in the cell beyond inflammasome activation? How does CARD8 fit into the context of a diverse array of inflammasome triggers? This kind of information would really help set the stage properly. The data in Figs. 3/4 could be strengthened by additional assays to measure inflammasome activation beyond IL-1β secretion and PI staining. Options include an IL-18 ELISA, LDH release assay, HMGB1 release assay, or caspase-1 cleavage assay (western blot). The provision of a second assay to corroborate inflammasome activation is consistent with field-specific standards.

    DETAILED U.P. ASSESSMENT: 

    OBJECTIVE CRITERIA (QUALITY) 

    1.   Quality: Experiments (1–3 scale; note: 1 is best on this scale) SCORE = 1.5

    ·     Figure by figure, do experiments, as performed, have the proper controls? [note: we use this 'figure-by-figure' section for broader detailed critiques, rather than only focusing on controls.

    ·       Fig. 1B – the cartoon introduces a 2nd PR cleavage site on CARD8 (site 88/89) that is not investigated further. Is this site relevant to this study? Do the amino acids at this site vary between humans and Old-world monkeys? The reader would benefit from some explanation about this protease cleavage site. 

    ·       Fig. 1C – We wondered whether treatment with a proteasome inhibitor could prevent degradation of CARD8 protein fragments and help us better understand cleavage patterns on western blots. Moreover, could the unknown band at ~40 kDa be further characterized, and does it relate to the N-terminal cleavage product?

    ·       Figs 1D/2B - The anti-vinculin loading control western blots for Figure 1D and Figure 2B are identical.

    ·       Fig. 3 – As mentioned above, abstract-level conclusions about inflammasome activation require better support. The data in Fig. 3 could be strengthened by additional assays to measure inflammasome activation beyond IL-1β secretion and PI staining. Options include an IL-18 ELISA, LDH release assay, HMGB1 release assay, or caspase-1 cleavage assay (western blot). The provision of a second assay to corroborate inflammasome activation is consistent with field-specific standards.

    ·       Figs. 4B/4C – "Similar to our observations with VbP, we found that IL-1β secretion and cell death were significantly reduced in Pam3CSK4-primed, HIV-1LAI or HIV-1LAI-VSVG infected CARD8 KO versus WT THP-1 cells (Figure 4C). These results indicate that HIV-1-induced inflammasome activation in THP-1 cells is dependent on CARD8." - This statement requires greater support demonstrating CARD8-dependent inflammasome activation. Inflammasome activation was still evident in the CARD8 KO cells. This analysis could benefit from corroboration with a second assay, as mentioned above. We wondered whether it would be feasible to employ a reconstructed inflammasome model, as reported in this recent paper:

    o    Qiyao Chai et al. A bacterial phospholipid phosphatase inhibits host pyroptosis by hijacking ubiquitin. Science 378, eabq0132(2022). DOI:10.1126/science.abq0132

    ·       Fig. 4D - We were once again curious about the identity of the unknown ~40 kDa band, which is clearly present in the CARD8 KO lysates. Perhaps this could be addressed in the Discussion.                                                                     

    Are specific analyses performed using methods that are consistent with answering the specific question?  

    ·     Is there appropriate technical expertise in the collection and analysis of data presented? 

    ·   Yes

    ·     Do analyses use the best-possible (most unambiguous) available methods quantified via appropriate statistical comparisons?  

    ·   Yes

    ·     Are controls or experimental foundations consistent with established findings in the field? A review that raises concerns regarding inconsistency with widely reproduced observations should list at least two examples in the literature of such results. Addressing this question may occasionally require a supplemental figure that, for example, re-graphs multi-axis data from the primary figure using established axes or gating strategies to demonstrate how results in this paper line up with established understandings. It should not be necessary to defend exactly why these may be different from established truths, although doing so may increase the impact of the study and discussion of discrepancies is an important aspect of scholarship.  

    ·   The provision of a second assay to corroborate inflammasome activation is consistent with field-specific standards.

    2.   Quality: Completeness (1–3 scale) SCORE = 2

    ·     Does the collection of experiments and associated analysis of data support the proposed title- and abstract-level conclusions? Typically, the major (title- or abstract-level) conclusions are expected to be supported by at least two experimental systems. 

    ·   The data in Figs 3/4 could be strengthened by additional assays to measure inflammasome activation beyond IL-1β secretion and PI staining. Options include an IL-18 ELISA, LDH release assay, HMGB1 release assay, or caspase-1 cleavage assay (western blot).

    ·     Are there experiments or analyses that have not been performed but if ''true'' would disprove the conclusion (sometimes considered a fatal flaw in the study)? In some cases, a reviewer may propose an alternative conclusion and abstract that is clearly defensible with the experiments as presented, and one solution to ''completeness'' here should always be to temper an abstract or remove a conclusion and to discuss this alternative in the discussion section. 

    ·   Beyond additional assays for inflammasome activation, we suggest that the authors could diversify the 'priming' treatments. For example, cells could be primed with LPS, poly I:C, or GM-CSF. Demonstrating CARD8-dependent inflammasome activation in conjunction with diverse stimuli will strengthen conclusions, and take away concerns about a TLR2-specific effect.

    3. Quality: Reproducibility (1–3 scale) SCORE = 1

    ·     Figure by figure, were experiments repeated per a standard of 3 repeats or 5 mice per cohort, etc.?

    ·   Sufficient biological replicates of all assays support the author's conclusions.    

    ·     Is there sufficient raw data presented to assess the rigor of the analysis? 

    ·   Yes

    ·     Are methods for experimentation and analysis adequately outlined to permit reproducibility? 

    ·   Yes

    ·     If a ''discovery' dataset is used, has a ''validation' cohort been assessed and/or has the issue of false discovery been addressed?  

    ·   N/A

    4. Quality: Scholarship (1–4 scale but generally not the basis for acceptance or rejection) SCORE = 1.5

    ·     Has the author cited and discussed the merits of the relevant data that would argue against their conclusion? 

    ·   Yes         

    ·     Has the author cited and/or discussed the important works that are consistent with their conclusion and that a reader should be especially familiar when considering the work? 

    ·     Yes

    ·     Specific (helpful) comments on grammar, diction, paper structure, or data presentation (e.g., change a graph style or color scheme) go in this section, but scores in this area should not be significant basis for decisions.

    ·       The following statement stimulated a lot of discussion amongst the students, who were concerned that the study doesn't really address pathogenesis: "Taken together, our work highlights how even minor, single amino acid changes can have dramatic, species-specific impacts on innate immune sensing and pathogenesis, and provides a model to explain, in part, the unique susceptibility of humans to HIV pathogenesis."

    ·       Minor points: We recommend changing the color scheme of graphs in Fig 3 to enhance readability. This could be achieved by color-coding, with one color per group (e.g. HIV-1LAI in blue and HIV-1LAI-VSVG in yellow).

    MORE SUBJECTIVE CRITERIA (IMPACT): 

    1.   Impact: Novelty/Fundamental and Broad Interest (1–4 scale) SCORE= 2.5

    A score here should be accompanied by a statement delineating the most interesting and/or important conceptual finding(s), as they stand right now with the current scope of the paper. A ''1'' would be expected to be understood for the importance by a layperson but would also be of top interest (have lasting impact) on the field.] 

    How big of an advance would you consider the findings to be if fully supported but not extended?

    ·       If properly supported by corroborating assays, these findings represent a significant advance in the field without further extension.

    2.   Impact: Extensibility (1–4 or N/A scale) SCORE =   2.5

    Has an initial result (e.g., of a paradigm in a cell line) been extended to be shown (or implicated) to be important in a bigger scheme (e.g., in animals or in a human cohort)?  This criterion is only valuable as a scoring parameter if it is present, indicated by the N/A option if it simply doesn't apply. The extent to which this is necessary for a result to be considered of value is important. It should be explicitly discussed by a reviewer why it would be required. What work (scope and expected time) and/or discussion would improve this score, and what would this improvement add to the conclusions of the study? Care should be taken to avoid casually suggesting experiments of great cost (e.g., ''repeat a mouse-based experiment in humans'') and difficulty that merely confirm but do not extend (see Bad Behaviors, Box 2)

    ·       The manuscript explores human vs. chimpanzee CARD8 and diverse lentiviruses. No further extension is provided to a bigger scheme.

    ·       We did wonder whether other non-lentiviral proteases could also cleave human CARD8. This would clearly add to our understanding of selective pressures that could have influenced CARD8 evolution in primates. Coronaviruses are mentioned in the discussion. Investigating the activity of coronavirus or enterovirus proteases against CARD8 homologs from different primates would be fascinating. Some clues may already exist in the following n-terminomics studies:

    o    Jagdeo JM, Dufour A, Klein T, Solis N, Kleifeld O, Kizhakkedathu J, Luo H, Overall CM, Jan E. N-Terminomics TAILS Identifies Host Cell Substrates of Poliovirus and Coxsackievirus B3 3C Proteinases That Modulate Virus Infection. J Virol. 2018 Mar 28;92(8):e02211-17. doi: 10.1128/JVI.02211-17. PMID: 29437971; PMCID: PMC5874412.

    o    Pablos I, Machado Y, de Jesus HCR, Mohamud Y, Kappelhoff R, Lindskog C, Vlok M, Bell PA, Butler GS, Grin PM, Cao QT, Nguyen JP, Solis N, Abbina S, Rut W, Vederas JC, Szekely L, Szakos A, Drag M, Kizhakkedathu JN, Mossman K, Hirota JA, Jan E, Luo H, Banerjee A, Overall CM. Mechanistic insights into COVID-19 by global analysis of the SARS-CoV-2 3CLpro substrate degradome. Cell Rep. 2021 Oct 26;37(4):109892. doi: 10.1016/j.celrep.2021.109892. Epub 2021 Oct 9. PMID: 34672947; PMCID: PMC8501228.

    o    Koudelka T, Boger J, Henkel A, Schönherr R, Krantz S, Fuchs S, Rodríguez E, Redecke L, Tholey A. N-Terminomics for the Identification of In Vitro Substrates and Cleavage Site Specificity of the SARS-CoV-2 Main Protease. Proteomics. 2021 Jan;21(2):e2000246. doi: 10.1002/pmic.202000246. Epub 2020 Nov 17. PMID: 33111431; PMCID: PMC7645863.

    o    Luo SY, Moussa EW, Lopez-Orozco J, Felix-Lopez A, Ishida R, Fayad N, Gomez-Cardona E, Wang H, Wilson JA, Kumar A, Hobman TC, Julien O. Identification of Human Host Substrates of the SARS-CoV-2 Mpro and PLproUsing Subtiligase N-Terminomics. ACS Infect Dis. 2023 Apr 14;9(4):749-761. doi: 10.1021/acsinfecdis.2c00458. Epub 2023 Apr 3. PMID: 37011043; PMCID: PMC10081575.

    o    Bell PA, Overall CM. No Substrate Left behind-Mining of Shotgun Proteomics Datasets Rescues Evidence of Proteolysis by SARS-CoV-2 3CLpro Main Protease. Int J Mol Sci. 2023 May 13;24(10):8723. doi: 10.3390/ijms24108723. PMID: 37240067; PMCID: PMC10218362.

    Competing interests

    The author declares that they have no competing interests.

  4. eLife

    eLife assessment

    The study shows that human inflammasome-forming sensor CARD8 contains a specific motif that allows cleavage by the proteases of HIV-1 and its direct precursor infecting chimpanzees. In comparison, CARD8 proteins from non-human primates contain changes in this motif and seem largely resistant to proteolytic activation. The results are important, and the data on the cleavage of CARD8 in HEK293T cells are convincing, while effects on inflammasome stimulation and cell death in primary viral target cells are insufficiently supported.

  5. eLife

    Reviewer #1 (Public Review):

    It has recently been shown that the HIV-1 protease can cleave and activate the inflammasome-forming sensor CARD8 upon treatment of infected cells with non-nucleoside reverse-transcriptase inhibitors (Wang et al., Science 2021). Here, Kulsuptrakul and colleagues show that the high susceptibility to proteolytic activation by the HIV-1 protease is a specific feature of human CARD8. They show that changes in human-specific F-F motif render the CARD8 protein of non-human primates largely resistant to cleavage. Interestingly, the protease of SIVcpz the direct precursor of pandemic HIV-1 strains are also capable of cleaving human but not chimpanzee CARD8. Thus, the authors propose that a human-specific CARD8 motif may contribute to the increased levels of inflammation and disease progression in HIV-infected humans compared to non-human primates that are naturally infected with SIV.

    Strengths of the study are that the authors convincingly show that a single human-specific amino acid change in CARD8 determines its susceptibility to cleavage by the HIV-1 protease and that the results shown are well controlled and presented. It is also interesting that SIVcpz can cleave human CARD8 and activate an inflammatory response. The major weakness is that it remains unclear whether HIV-1 of SIVcpz may induce CARD8-dependent inflammatory responses in primary CD4+ T cells or macrophages. The most relevant setting in the study was the infection of THP-1 cells with the T cell line-adapted X4-tropic HIV-1 LAI molecular clone. However, the effects on cell death were modest (Figure 3A) and on IL-1ß secretion was not dose-dependent (Figure 3B). Altogether, stronger effects were observed with VSV-G-pseudotyped HIV-1 and only those were used in subsequent experiments involving human CARD8 cleavage mutants (Figure 4). Additional evidence that primary HIV-1 molecular clones and/or SIVcpz may indeed induce CARD8-dependent inflammatory responses in primary viral target cells would greatly increase the significance of the study. In the absence of such data, conclusions about the potential role of CARD8 sensing of the viral protease for the pathogenesis of AIDS should be cautioned throughout.

  6. eLife

    Reviewer #2 (Public Review):

    The HIV inflammasome sensor CARD8 senses intracellular HIV-1 protease activity through direct cleavage by HIV-1 protease between the F59 and F60 positions in the human CARD8 protein. The authors show that the F60 position is variable across non-human primate species that show varying levels of cleavage efficacy. They also posit that inflammasome induction may be dependent upon Toll-like receptor signaling.

    Strengths: The authors are able to show that both HIV-1 and HIV-2 cleave and activate the human CARD8 inflammasome. The authors also demonstrate that changes to the 60th position of CARD8 cause a decrease in cleavage efficacy in vitro by HIV-1.

    Weaknesses: The study is limited to the introduction of a few mutations in human CARD8 and their cleavage and activation by HIV. The physiological relevance remains unclear without direct investigation of different versions of simian CARD8 protein and SIVs in T cells and macrophages.

  7. eLife

    Reviewer #3 (Public Review):

    The work provides interesting information on human CARD8 for its role in sensing HIV-1 infection and subsequent inflammasome activation as a possible cause of HIV pathogenesis. Proteolytic cleavage at the N-terminus of human CARD8 was confirmed by western blotting of HEK293T cells co-transfected with a CARD8-expression vector and HIV proviral constructs. This analysis also allowed the definition of substrate/enzyme specificity - only human CARD8 is susceptible to proteases derived from HIV and SIV; CARD8s of other gibbons and Old-World monkeys are not due to a single amino acid variation at the P1' position. One thing to note is that the efficiency of this cleavage reaction appeared fairly low because this product (33 kD in Figure 1B) only consisted of a small portion of total CARD8 antibody reactive proteins. To define the correlation between HIV infection and CARD8-mediated inflammasome activation in THP-1 model cells, authors used cell death by propidium iodide staining and IL-1β secretion as inflammasome activation biomarkers. However, cell death measured by propidium iodide staining could be caused by a variety of factors/pathways and thus not specific for pyroptosis resulting from CARD8-mediated inflammasome activation, complicating data interpretation. With IL-1β secretion as an indicator, authors concluded that TLR2 priming (by Pam3CSK4) is required for inflammasome activation by HIV infection, which raises a question of whether HIV infection alone is sufficient at CARD8 activation in THP-1 cells. Data obtained with clonal CARD8 knockout THP cells by CRISPR/cas9 provide clean results confirming that CARD8-mediated inflammasome activation contributes to IL-1β secretion and cell death in parallel with other inflammasome pathways. Data obtained from CARD8KO cells complemented with CARD8 proteins with various substrate sequences provided vital evidence showing that proteolysis at the N-terminus of human CARD8 by HIV-1 protease contributed to CARD8-mediated inflammasome activation although at levels much lower than VbP-stimulated inflammasome activation that appeared to be independent of HIV PR catalyzed N-terminus cleavage. Taken together, this report presents evidence that supports the involvement of human CARD8-mediated inflammasome activation via the N-terminus cleavage by HIV PR, which added valuable information to advance the understanding of pathogenesis caused by HIV infection. However, how much it contributes to HIV-1 pathogenesis remains to be further defined as the contributions are expected to be diverse among cell types and homeostatic stages of infected cells.

  8. Version published to 10.1101/2022.10.04.510817v1 on bioRxiv