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The Nef protein of human and primate lentiviruses is a key factor in HIV/SIV pathogenesis. Here we report that Nef associates with two different kinases, forming a multiprotein complex at the far N-terminus of the viral protein. One of the kinases was identified as Lck, whereas the second protein was found to be a serine kinase that phosphorylated Nef and Lck in vitro and could be discriminated from the serine kinase identified previously. The Nef-associated kinase complex (NAKC) was demonstrated in COS cells, in HIV-infected cells, and in vitro using recombinant Lck and Nef proteins. Deletion of a short amphipathic alpha-helix in the N-terminus, which was found to be conserved in all Nef proteins, inhibited association of the NAKC and significantly reduced virion infectivity.

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Increasing evidence indicates that inflammation of visceral organs is significantly affected by the autonomic nervous system. Such neuroimmune interactions have not been studied in the kidney. Here, we show that the rat kidney is innervated by both tyrosine hydroxylase-positive sympathetic efferent nerve fibers and calcitonin gene-related peptide-positive primary afferent nerve fibers, both of which are found in proximity to macrophages and dendritic cells. Complete surgical bilateral renal denervation was performed 2 d before glomerulonephritis was induced by injecting the monoclonal anti-Thy-1.1 antibody OX-7. Denervation significantly reduced albuminuria, mesangiolysis, formation of microaneurysms, deposition of glomerular collagen IV, and expression of TGF-␤ compared with sham-operated controls. Accordingly, inflammation, identified by accumulation of interstitial macrophages and renal expression of TNF-␣, and mesangial cell proliferation were significantly reduced. These findings indicate that autonomic renal denervation ameliorates and, by inference, innervation exacerbates acute inflammation in the kidney; therefore, neurotransmitters or neuropeptides and their receptors might represent novel targets for the treatment of acute glomerulonephritis.

The anti-inflammatory and antiapoptotic heme degrading enzyme heme oxygenase-1 (HO-1) has been shown recently to interfere with replication of hepatitis C virus (HCV). We investigated the effect of HO-1 products carbon monoxide (CO), iron and biliverdin on HCV replication using the replicon cell lines Huh-5-15 and LucUbiNeo-ET, stably expressing HCV proteins NS3 through NS5B. Incubation of these cell lines in the presence of the CO donor methylene chloride transiently reduced HCV replication, whereas an increase of iron in cell culture by administration of The heme-degrading enzyme heme oxygenase-1 (HO-1) exerts anti-inflammatory and antiapoptotic effects in vitro and in vivo. Induction or overexpression of HO-1 protects kidneys from acute ischemic failure 6 or ischemia-reperfusion injury, 7 cardiac xenografts from rejection, 8 and livers from ischemia-reperfusion injury caused by either transplantation 9 or hemorrhage/resuscitation, 10 as well as from apoptotic damage. 11 Degradation of heme by heme oxygenases results in the production of carbon monoxide (CO), free iron, and biliverdin. HO-1, in contrast to the isoforms HO-2 and HO-3, is inducible by various stimuli, 12,13 such as cobalt-protoporphyrin-IX (CoPP), 14,15 but also by hypoxia, which can be induced by, for example, high amounts of CO. 16 Of the HO-1 products, CO and biliverdin seem to be the major mediators of protective HO-1 effects within the liver. 17-19 CO application in vitro or in vivo can be achieved by special

and are common opportunistic bacterial and fungal pathogens, respectively. They often coexist in airways of immunocompromised patients and individuals with cystic fibrosis, where they form biofilms and cause acute and chronic illnesses. Hence, the interactions between them have long been of interest and it is known that can inhibit We have approached the definition of the inhibitory molecules by studying 24 mutants with various virulence genes deleted for the ability to inhibit biofilms. The ability of cells or their extracellular products produced during planktonic or biofilm growth to affect biofilm metabolism or planktonic growth was studied in agar and liquid assays using conidia or hyphae. Four mutants, the, ,, and mutants, were shown to be defective in various assays. This suggested the siderophore pyoverdine as the key inhibitory molecule, although additional quorum sensing-regulated factors likely contribute to the deficiency of the latter two mutants. Studies of pure pyoverdine substantiated these conclusions and included the restoration of inhibition by the pyoverdine deletion mutants. A correlation between the concentration of pyoverdine produced and antifungal activity was also observed in clinical isolates derived from lungs of cystic fibrosis patients. The key inhibitory mechanism of pyoverdine was chelation of iron and denial of iron to Interactions between human pathogens found in the same body locale are of vast interest. These interactions could result in exacerbation or amelioration of diseases. The bacterium affects the growth of the fungus Both pathogens form biofilms that are resistant to therapeutic drugs and host immunity. and biofilms are found , e.g., in the lungs of cystic fibrosis patients. Studying 24 mutants, we identified pyoverdine as the major anti- compound produced by Pyoverdine captures iron from the environment, thus depriving of a nutrient essential for its growth and metabolism. We show how microbes of different kingdoms compete for essential resources. Iron deprivation could be a therapeutic approach to the control of pathogen growth.

TNF-α has been clearly identified as central mediator of T cell activation-induced acute hepatic injury in mice, e.g., Con A hepatitis. In this model, liver injury depends on both TNFRs, i.e., the 55-kDa TNFR1 as well as the 75-kDa TNFR2. We show in this report that the hepatic TNFRs are not transcriptionally regulated, but are regulated by receptor shedding. TNF directly mediates hepatocellular death by activation of TNFR1 but also induces the expression of inflammatory proteins, such as cytokines and adhesion molecules. Here we provide evidence that resistance of TNFR1−/− and TNFR2−/− mice against Con A hepatitis is not due to an impaired production of the central mediators TNF and IFN-γ. Con A injection results in a massive induction of ICAM-1, VCAM-1, and E-selectin in the liver. Lack of either one of both TNFRs did not change adhesion molecule expression in the livers of Con A-treated mice, presumably reflecting the fact that other endothelial cell-activating cytokines up-regulated adhesion molecule expression. However, treatment of TNFR1−/− and TNFR2−/− mice with murine rTNF revealed a predominant role for TNFR1 for the induction of hepatic adhesion molecule expression. Pretreatment with blocking Abs against E- and P-selectin or of ICAM−/− mice with anti-VCAM-1 Abs failed to prevent Con A hepatitis, although accumulation of the critical cell population, i.e., CD4+ T cells was significantly inhibited. Hence, up-regulation of adhesion molecules during acute hepatitis unlikely contributes to organ injury but rather represents a defense mechanism.