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

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. 9 NOD/SCID/γcnil/nil female mice at 3 weeks of age were irradiated at which point mixed donor human cord blood CD34+ stem cells were injected for the generation of humanized mice. There were 3 animals per group, in 3 groups total. Recombinant human FLT-3 ligand (rFLT-3L) N=3, rFLT-3L+HIV N=2, rFLT-3L+HIV+VX-765 N=3. Splenic tissues were harvested from euthanized animals on day 14. mRNA was examined by Next Generation Sequence (NGS) analysis.