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Inhibition of Caspase-1 limits CD4+ T cell loss and restores host anti-retroviral function in HIV-1 infected humanized mice with augmented lymphoid tissue

ABSTRACT: The study of HIV infection and pathogenicity in physical reservoirs requires a biologically relevant model which resembles the human immune system and physiology. The human immune system (HIS) mouse is an established model of HIV infection1–3, but defects in immune tissue reconstitution remain a challenge for examining pathology in tissues1,3–7. Herein we show that exogenous injection of the human cytokine FLT-3L into the hematopoietic stem cell (HSC) cord blood HIS mouse model significantly expanded the total area of axillary lymph nodes and the absolute number of circulating human T cells, thus enabling us to visualize and quantify HIV infectivity in the secondary lymphoid tissues of the spleen and axillary node. Further, we detected cell death and human T cell depletion in tissues, consistent with HIV pathogenesis. Treatment with the Caspase-1 inhibitor VX-765 restored CD4+ T donor cells and decreased plasma viral load as measured by gag qPCR, and apoptosis in the spleen. In situ hybridization further demonstrated a decrease in viral RNA in both the spleen and axillary lymph nodes. Transcriptomic analysis revealed that in vivo inhibition of caspase-1 led to an upregulation in host HIV restriction factors including APOBR, SAMHD1 and APOBEC3A (study design depicted in graphical abstract). These findings demonstrate that exogenous rFLT-3L as a mechanism to enhance human immune system characteristics in HIS mice. These enhancements will support investigations of HIV pathogenesis and immune outcomes in tissue compartments. Targeting inflammasome pathways with VX-765 in HIS mice treated with rFLT-3L preserved T cell populations and decreased viral load after HIV infection.

ORGANISM(S): Mus musculus

PROVIDER: GSE213865 | GEO | 2024/05/08

REPOSITORIES: GEO

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Project description:Macrophages provide an interface between innate and adaptive immunity and are important long-lived reservoirs for Human Immunodeficiency Virus Type-1 (HIV-1). Multiple genetic networks involved in regulating signal transduction cascades and immune responses in macrophages are coordinately modulated by HIV-1 infection. To evaluate complex interrelated processes and to assemble an integrated view of activated signaling networks, a systems biology strategy was applied to genomic and proteomic responses by primary human macrophages over the course of HIV-1 infection. Macrophage responses, including cell cycle, calcium, apoptosis, mitogen-activated protein kinases (MAPK), and cytokines/chemokines, to HIV-1 were temporally regulated, in the absence of cell proliferation. In contrast, Toll-like receptor (TLR) pathways remained unaltered by HIV-1, although TLRs 3, 4, 7, and 8 were expressed and responded to ligand stimulation in macrophages. HIV-1 failed to activate phosphorylation of IRAK-1 or IRF-3, modulate intracellular protein levels of Mx1, an interferon-stimulated gene, or stimulate secretion of TNF, IL-1b, or IL-6. Activation of pathways other than TLR was inadequate to stimulate, via cross-talk mechanisms through molecular hubs, the production of proinflammatory cytokines typical of a TLR response. HIV-1 sensitized macrophage responses to TLR ligands, and the magnitude of viral priming was related to virus replication. HIV-1 induced a primed, proinflammatory state, M1HIV, which increased the responsiveness of macrophages to TLR ligands. HIV-1 might passively evade pattern recognition, actively inhibit or suppress recognition and signaling, or require dynamic interactions between macrophages and other cells, such as lymphocytes or endothelial cells. HIV-1 evasion of TLR recognition and simultaneous priming of macrophages may represent a strategy for viral survival, contribute to immune pathogenesis, and provide important targets for therapeutic approaches. Affymetrix arrays were used to identify genomic macrophage response to HIV during viral spread in culture. Experiment Overall Design: An HIV-1 spreading infection was established in primary human macrophages. RNA was extracted from both viral- and mock-infected macrophages cultures over 7 days and hybridized to Affymetrix HG-U95Av2 GeneChips for analysis.

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Inhibition of Caspase-1 limits CD4+ T cell loss and restores host anti-retroviral function in HIV-1 infected humanized mice with augmented lymphoid tissue

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