The anti-caspase 1 inhibitor VX-765 reduces immune activation, CD4+ T cell depletion, viral load, and total HIV-1 DNA in HIV-1 infected humanized mice

  1. Mathieu Amand
  2. Philipp Adams
  3. Rafaela Schober
  4. Gilles Iserentant
  5. Jean-Yves Servais
  6. Michel Moutschen
  7. Carole Seguin-Devaux

  • Curated by eLife

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    The present study presents the important finding that HIV infection activates the NLRP3, IFI16, and AIM 2 inflammasome pathways and that treatment with the anti-caspase 1 inhibitor VX-765 moderately reduces inflammasome activation and CD4 T cell depletion in a humanized NSG mouse model. The evidence supporting that inflammasome activation may play an important role in CD4 T cell depletion and that anti-caspase-1 inhibitors may reduce harmful inflammation is for the most part solid, although not always complete. The results will be of interest to scientists and physicians working on HIV immunology, pathogenesis and cure strategies.

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Abstract

HIV-1 infection results in the activation of inflammasome that may facilitate viral spread and establishment of viral reservoirs. We evaluated the effects of the caspase-1 inhibitor VX-765 on HIV-1 infection in humanized NSG mice engrafted with human CD34 + hematopoietic stem cells. Expression of caspase-1, NLRP3, and IL-1β was increased in lymph nodes and bone marrow between day 1 and 3 after HIV-1 infection (mean fold change (FC) of 2.08, 3.23, and 6.05, p<0.001, respectively). IFI16 and AIM2 expression peaked at day 24 and coincides with increased IL-18 levels (6.89 vs 83.19 pg/ml, p=0.004), increased viral load and CD4 + T cells loss in blood (p<0.005 and p<0.0001, for the spleen respectively). Treatment with VX-765 significantly reduced TNF-α at day 11 (0.47 vs 2.2 pg/ml, p=0.045), IL-18 at day 22 (7.8 vs 23.2 pg/ml, p=0.04), CD4 + T cells (44.3% vs 36,7%, p=0.01), viral load (4.26 vs 4.89 log 10 copies/ml, p=0.027), and total HIV-1 DNA in the spleen (1 054 vs 2 889 copies /10 6 cells, p=0.029). We demonstrated that targeting inflammasome activation early after infection may represent a therapeutic strategy towards HIV cure to prevent CD4 + T cell depletion and reduce immune activation, viral load, and the HIV-1 reservoir formation.

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  1. Version published to 10.7554/elife.83207 on eLife
  2. eLife

    eLife assessment

    The present study presents the important finding that HIV infection activates the NLRP3, IFI16, and AIM 2 inflammasome pathways and that treatment with the anti-caspase 1 inhibitor VX-765 moderately reduces inflammasome activation and CD4 T cell depletion in a humanized NSG mouse model. The evidence supporting that inflammasome activation may play an important role in CD4 T cell depletion and that anti-caspase-1 inhibitors may reduce harmful inflammation is for the most part solid, although not always complete. The results will be of interest to scientists and physicians working on HIV immunology, pathogenesis and cure strategies.

  3. eLife

    Reviewer #1 (Public Review):

    In this manuscript, the authors present a study on the humanized mouse model of HIV, in which the major focus is inflammasome activation during acute infection and the potential for blocking this activation. They describe the mouse model as sufficient to study inflammasome activity after HIV infection and proceed to demonstrate potentially beneficial effects of a caspase-1 inhibitor, VX-765, given during acute infection resulting in mildly reduced viral load and increased CD4 T cell preservation.

    The authors clearly demonstrate established HIV infection in huNSG mice through detection of plasma viremia, viral RNA/DNA in tissue and depletion of CD4 T cells. Furthermore, they show moderate but inconsistent increases in expression of inflammasome-related genes using qPCR across multiple tissues and timepoints. As expected, the authors found increased levels of inflammatory cytokines, particularly IL-18, during acute viral infection.

    Systemic IL-18 levels are significantly reduced by VX-765, demonstrating clear in vivo capacity to impact inflammasome-related cytokines. Furthermore, there appears to be a statistically significant preservation of CD4 T cell populations in VX-765-treated animals, although this preservation is inconsistent across different tissues and may not be to a biologically relevant degree. Finally, VX-765 appears to significantly decrease plasma viral load at day 22 post-infection and potentially results in lower HIV DNA levels in the spleen. Finally, the manuscript demonstrates reduced caspase-1 activity after VX-765 treatment, but this finding is limited to CD11c+ and CD14+ cells with no impact found within CD4 and CD8 T cells, and the authors acknowledge that they may be unable to detect caspase-1 activity in CD4 and CD8 T cells after HIV infection.

    Although the study is interesting, there are several important comments and potential caveats/limitations that must be addressed, including for the correlations between AIM2 and IFI6 with viral loads and CD4 T cells that appear strongly driven by measurements at day 0 post-infection; multiple cytokine measurements that appear to be below the manufacturer's described limit of detection for the assay described; a lack of measurable caspase activity in T cells; some inconsistency between DNA or RNA content and plasma viremia.

  4. eLife

    Reviewer #2 (Public Review):

    The manuscript nicely describes the use of a humanized NSG mice HIV model that mimics HIV infection in humans. Using this model, the Authors were able to clearly illustrate substantial evidence of inflammasome activation in HIV infection. This was done via analysis of mRNA transcripts of proteins pivotal of NLRP3, IFI16, and AIM 2 inflammasome pathway activation, and also measurement of plasma level of various inflammatory cytokines via multiplex U-PLEX Biomarker assay kit. Furthermore, they elaborated clearly on the negative correlation between inflammasome activation and some inflammatory cytokines with the percentage of CD4 T cells. From this study, the increase in inflammasome activation contributed remarkably to CD4 T cell depletion, beginning from three days post infection and reaching the climax by day 28. Interestingly, the authors were able to elucidate a decrease in inflammasome activation and CD4 T cell depletion with the use of anti-caspase 1 inhibitor VX-765.

    The kinetics of viremia and CD4 T cell depletion, as well as levels of HIV RNA expression in different compartments (Figure Suppl 1 and 2) was a clever illustration of HIV dissemination in early infection. Furthermore, the evaluation of gene expression in the different compartments (lung, bone marrow, lymph node, and spleen) using qPCR at different time points of the study was supportive at the molecular level of inflammasome activation in early HIV infection (Figure 1, Figure Suppl 3) gave more credibility to the study. it was interesting to see good illustrations of different effector molecules(cytokines) of inflammasome activation at different time points of the study. The choice of using an anti-caspase 1 inhibitor VX-765 in HIV infection was a smart idea to limit the inflammatory changes and CD4 T cell death in HIV infection. The graphs supported their claim as we could see a decrease IL1B, and IL18 (Figure 4) which are key effector molecules during inflammasome activation. They also showed a decrease in CD4 T cell depletion with VX-765 compared to the negative control (Figure 5).

    Despite the novelty and strengths of the study, there were some weaknesses on the design of the study. The Authors explained well in the introduction the elimination of HIV reservoirs as a key factor for HIV cure. Also, the Authors reported anti-caspase 1 inhibitor VX-765 reduces HIV reservoirs. However, in the study the Authors did not quantify the different HIV reservoirs (For example Central memory and effector memory CD4 T cells) and the effect of VX-765 on the population of these HIV reservoirs Furthermore the expression of genes associated with inflammasome activation in HIV infection was well presented. However, there was no gene expression profiling after administration of the anti-caspase 1 inhibitor VX-765, which would have been a better method to evaluate the effect of the drug on inflammasome activation

  5. Version published to 10.1101/2022.09.01.502964v1 on bioRxiv