Tim-3 expression defines a novel population of dysfunctional T cells with highly elevated frequencies in progressive HIV-1 infection

Progressive loss of T cell functionality is a hallmark of chronic infection with human immunodeficiency virus 1 (HIV-1). We have identified a novel population of dysfunctional T cells marked by surface expression of the glycoprotein Tim-3. The frequency of this population was increased in HIV-1–infected individuals to a mean of 49.4 ± SD 12.9% of CD8+ T cells expressing Tim-3 in HIV-1–infected chronic progressors versus 28.5 ± 6.8% in HIV-1–uninfected individuals. Levels of Tim-3 expression on T cells from HIV-1–infected inviduals correlated positively with HIV-1 viral load and CD38 expression and inversely with CD4+ T cell count. In progressive HIV-1 infection, Tim-3 expression was up-regulated on HIV-1–specific CD8+ T cells. Tim-3–expressing T cells failed to produce cytokine or proliferate in response to antigen and exhibited impaired Stat5, Erk1/2, and p38 signaling. Blocking the Tim-3 signaling pathway restored proliferation and enhanced cytokine production in HIV-1–specific T cells. Thus, Tim-3 represents a novel target for the therapeutic reversal of HIV-1–associated T cell dysfunction

Studies of the incretins, glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide, and their receptors

grantor: University of TorontoGLP-1 (Glucagon-like peptide-1) and GIP (Glucose-dependent insulinotropic polypeptide) are intestinal hormones that potentiate glucose-stimulated insulin secretion from pancreatic $\beta$ cells. GLP-1, in particular, is at the forefront of diabetes research due to its antidiabetogenic actions in Type 2 diabetics. Previous studies demonstrated that GLP-1R$-$/$-$ mice exhibit mild diabetes despite upregulation of GIP secretion and insulinotropic action. GLP-1R$-$/$-$ mice were found to have diminished pancreatic insulin protein and mRNA levels, which may explain in part, the inability of GIP to fully compensate for the absence of GLP-1 activity in these mice. An evolutionary approach was used to study the functional determinants of GLP-1. The biological activities of three novel Xenopus laevis GLP-1-like peptides with $\sim$70% amino acid identity to human GLP-1 were found to be similar to that of human GLP-1. Furthermore residues at positions 12 and 23 of the Xenopus peptides, corresponding to positions 19 and 29 of mammalian GLP-1 were identified as critical to peptide activity. Study of GIP/GLP-1 receptor chimeras localized an activation domain of a GIP/GLP-1 receptor to three residues at the amino-terminus of the first transmembrane domain.M.Sc

Receptor-binding loops in alphacoronavirus adaptation and evolution

International audienceRNA viruses are characterized by a high mutation rate, a buffer against environmental change. Nevertheless, the means by which random mutation improves viral fitness is not well characterized. Here we report the X-ray crystal structure of the receptor-binding domain (RBD) of the human coronavirus, HCoV-229E, in complex with the ectodomain of its receptor, aminopeptidase N (APN). Three extended loops are solely responsible for receptor binding and the evolution of HCoV-229E and its close relatives is accompanied by changing loop-receptor interactions. Phylogenetic analysis shows that the natural HCoV-229E receptor-binding loop variation observed defines six RBD classes whose viruses have successively replaced each other in the human population over the past 50 years. These RBD classes differ in their affinity for APN and their ability to bind an HCoV-229E neutralizing antibody. Together, our results provide a model for alphacoronavirus adaptation and evolution based on the use of extended loops for receptor binding

Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor (-/-) mice

Incretins are gastrointestinal hormones that act on the pancreas to potentiate glucose-stimulated insulin secretion. Despite the physiological importance of the enteroinsular axis, disruption of glucagon-like peptide (GLP)-1 action is associated with only modest glucose intolerance in GLP-1 receptor -/- (GLP-1R -/-) mice. me show here that GLP-1R -/- mice exhibit compensatory changes in the enteroinsular axis via increased glucose-dependent insulinotropic polypeptide (GIP) secretion and enhanced GIP action. Serum GIP levels in GLP-1R -/- mice were significantly elevated versus those in +/+ control mice after an oral glucose tolerance test (369 +/- 40 vs. 236 +/- 28 pmol/l; P less than or equal to 0.02). Furthermore, GIP perfusion of mice pancreas and isolated islets in the presence of elevated glucose concentrations elicited a significantly greater insulin response in GLP-1R -/- than in +/+ mice (P less than or equal to 0.02-0.05). In contrast, no significant perturbation in the insulin response to perfused glucagon was detected under conditions of low (4.4 mmol/l) or high (16.6 mmol/l) glucose in GLP-1R -/- mice. Total pancreatic insulin but not glucagon content was significantly reduced in GLP-1R -/- compared with in +/+ mice (77 +/- 9 vs. 121 +/- 10 pmol/mg protein; P less than or equal to 0.005). These observations suggest that upregulation of the GIP component of the enteroinsular axis, at the levels of GLP secretion and action, modifies the phenotype resulting from interruption of the insulinotropic activity of GLP-1 in vivo