A Delayed HIV Infection Model with the Homeostatic Proliferation of CD4^(+)T Cells

In this paper,we investigate a delayed HIV infection model that considers the homeostatic prolif-eration of CD4^(+)T cells.The existence and stability of uninfected equilibrium and infected equilibria(smaller and larger ones)are studied by analyzing the characteristic equation of the system.The intracellular delay does not affect the stability of uninfected equilibrium,but it can change the stability of larger positive equilibrium and Hopf bifurcation appears inducing stable limit cycles.Furthermore,direction and stability of Hopf bifur-cation are well investigated by using the central manifold theorem and the normal form theory.The numerical simulation results show that the stability region of larger positive equilibrium becomes smaller as the increase of time delay.Moreover,when the maximum homeostatic growth rate is very small,the larger positive equilibrium is always stable.On the contrary,when the rate of supply of T cells is very small,the larger positive equilibrium is always unstable.

Nanoparticles (NPs)-mediated Siglec15 silencing and macrophage repolarization for enhanced cancer immunotherapy

cell infiltration and proliferation in tumor tissues are the main factors that significantly affect the therapeutic outcomes of cancer immunotherapy.Emerging evidence has shown that interferon-gamma(IFN)could enhance CXCL9 secretion from macrophages to recruit T cells,but Siglec15 expressed on TAMs can attenuate T cell proliferation.Therefore,targeted regulation of macrophage function could be a promising strategy to enhance cancer immunotherapy via concurrently promoting the infiltration and proliferation of T cells in tumor tissues.We herein developed reductionresponsive nanoparticles(NPs)made with poly(disulfide amide)(PDSA)and lipid-poly(ethylene glycol)(lipid-PEG)for systemic delivery of Siglec15 siRNA(siSiglec15)and IFN for enhanced cancer immunotherapy.After intravenous administration,these cargo-loaded could highly accumulate in the tumor tissues and be efficiently internalized by tumor-associated macrophages(TAMs).With the highly concentrated glutathione(GSH)in the cytoplasm to destroy the nanostructure,the loaded IFN and si-Siglec15 could be rapidly released,which could respectively repolarize macrophage phenotype to enhance CXCL9 secretion for T cell infiltration and silence Siglec15 expression to promote T cell proliferation,leading to significant inhibition of hepatocellular carcinoma(HCC)growth when combining with the immune checkpoint inhibitor.The strategy developed herein could be used as an effective tool to enhance cancer immunotherapy.

Cutaneous Dengue Virus Inoculation Triggers Strong B Cell Reactions but Contrastingly Poor T Cell Responses

Dengue is a global health problem without current specific treatment nor safe vaccines available.While severe dengue is related to pre-existing non-neutralizing dengue virus(DENV)antibodies,the role of T cells in protection or pathology is unclear.Using cutaneous DENV infection in immunocompetent mice we previously showed the generation of PNA+germinal centers(GCs),now we assessed the activation and proliferation of B and T cells in draining lymph nodes(DLNs).We found a drastic remodelling of DLN compartments from 7 to 14 days post-infection(dpi)with greatly enlarged B cell follicles,occupying almost half of the DLN area compared to*24%in na?ve conditions.Enormous clusters of proliferating(Ki-67+)cells inside B follicles were found 14 dpi,representing*33%of B cells in DLNs but only*2%in noninfected mice.Inside GCs,we noticed an important recruitment of tingle body macrophages removing apoptotic cells.In contrast,the percentage of paracortex area and total T cells decreased by 14–16 dpi,compared to controls.Scattered randomly distributed Ki-67+T cells were found,similar to non-infected mice.CD69 expression by CD4+and CD8+T cells was minor,while it was remarkable in B cells,representing 1764.7%of change from basal levels 3 dpi.The apparent lack of T cell responses cannot be attributed to apoptosis since no significant differences were observed compared to noninfected mice.This study shows massive B cell activation and proliferation in DLNs upon DENV infection.In contrast,we found very poor,almost absent CD4+and CD8+T cell responses.