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.
HIV; anti-inflammatory agents; cytokine; hiv reservoirs; immunology; inflammasome inhibitors; inflammation; mouse; pyroptosis; Inflammasomes; interleukin-1beta-converting enzyme inhibitor; Interleukin-18; belnacasan; Mice; Humans; Animals; Inflammasomes/metabolism; Viral Load; T-Lymphocytes/metabolism; CD4-Positive T-Lymphocytes; HIV-1; HIV Infections; T-Lymphocytes; Neuroscience (all); Biochemistry, Genetics and Molecular Biology (all); Immunology and Microbiology (all); General Immunology and Microbiology; General Biochemistry, Genetics and Molecular Biology; General Medicine; General Neuroscience
Abstract :
[en] 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.
Disciplines :
Immunology & infectious disease
Author, co-author :
Amand, Mathieu ; Université de Liège - ULiège > Département des sciences cliniques > GIGA-R : Immunopathologie - Maladies infectieuses et médecine interne générale ; Department of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, Luxembourg
Adams, Philipp; Department of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, Luxembourg
Schober, Rafaela; Department of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, Luxembourg
Iserentant, Gilles; Department of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, Luxembourg
Servais, Jean-Yves; Department of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, Luxembourg
Moutschen, Michel ; Centre Hospitalier Universitaire de Liège - CHU > > Service des maladies infectieuses - médecine interne
Seguin-Devaux, Carole ; Department of Infection and Immunity, Luxembourg Institute of Health, Esch sur Alzette, Luxembourg
Language :
English
Title :
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.
We acknowledge Charlène Vershueren and Quentin Etienne for their technical assistance in animal experimentation. The following reagent was obtained through the NIH HIV Reagent Program, Division of AIDS, NIAID, NIH: Human Immunodeficiency Virus 1 (HIV-1), Strain JR-CSF Infectious Molecular Clone (pYK-JRCSF), ARP-2708, contributed by Dr Irvin S Y Chen and Dr Yoshio Koyanagi."Fonds National de la Recherche Luxembourg AFR PhD ID 10111126 Philipp AdamsFonds National de la Recherche Luxembourg Next Immune DTU PRIDE ID 11012546 Rafaela Schober.
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