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

Mathieu Amand, Philipp Adams, Rafaela Schober, Gilles Iserentant, Jean-Yves Servais, Michel Moutschen, Carole Seguin-Devaux*

*Corresponding author for this work

Research output: Contribution to journalArticleResearchpeer-review

7 Citations (Scopus)

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 /106 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.

Original languageEnglish
Article numbere83207
JournaleLife
Volume12
DOIs
Publication statusPublished - 17 Feb 2023

Keywords

  • Mice
  • Humans
  • Animals
  • Inflammasomes/metabolism
  • HIV-1
  • Interleukin-18
  • Viral Load
  • HIV Infections
  • T-Lymphocytes/metabolism
  • CD4-Positive T-Lymphocytes

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