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bioRxiv · 10.1101/2022.09.01.502964

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

Amand, M.·Adams, P.·Schober, R.·Iserentant, G.·Servais, J.-Y.·Moutschen, M.·Seguin-Devaux, C.
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Abstract

BackgroundHIV-1 infection results in the activation of inflammasome involving NLRP3, IFI16, caspase-1 and release of IL-1 {beta} and IL-18. Early inflammasome activation may facilitate viral spread and establishment of the viral reservoir. We evaluated the effect of the caspase-1 inhibitor VX-765 on virological and immunological parameters after HIV-1 infection in humanized mice. MethodsNSG mice were engrafted with human CD34+ hematopoietic stem cells and were infected with HIV-1 JRCSF. 15 mice were first sacrificed serially to investigate kinetics of the HIV-1 related inflammasome activation. Infected mice (n=24) were then treated with VX-765 or vehicle from day 1 post infection for 21 days. Blood and organs were collected at different time points, and analysed for inflammasome genes expression, cytokines levels, viral load, CD4 cell count, and total HIV-1 DNA. ResultsExpression of caspase-1, NLRP3 and IL1-{beta} was increased in lymph nodes and bone marrow on day 1 and 3 post infection (mean fold change (FC) of 2.08, 3.23, and 6.05, p< 0.001 respectively between day 1 and 3). IFI16 expression peaked at D24 in lymph node and bone marrow (FC 1.49 and 1.64, p<0.05) and coincides with increased IL-18 levels in plasma (6.89 vs. 83.19 pg/ml, p=0.004). AIM2 and IFI16 expression correlated with increased viral load in tissues (p<0.005 for the spleen) and loss of CD4+ T cells percentage in blood (p<0.0001 for the spleen). Treatment with VX-765 significantly reduced TNF- 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) and the CD4/CD8 ratio (0.92 vs 0.67, p=0.005) in plasma. Importantly, viral load (4.26 vs. 4.89 log 10 copies/ml, p=0.027) and total HIV-1 DNA (1 054 vs. 2 889 copies /106 cells, p=0.029) were decreased in VX-765-treated mice as compared to vehicle-treated mice. Discussionwe report here an early inflammasome activation before detectable viral dissemination in humanized mice. We demonstrated that targeting inflammasome activation early after HIV-1 infection may represent a potential therapeutic strategy to prevent CD4+ T cell depletion as well as to reduce immune activation, viral load and the HIV-1 reservoir formation.

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Amand, M., Adams, P., Schober, R., Iserentant, G., Servais, J.-Y., Moutschen, M., Seguin-Devaux, C.. 2022-09-04. 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. https://doi.org/10.1101/2022.09.01.502964

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