Modulation of HIV-1 replication in primary dendritic cells in contact with autologous CD4 T-lymphocytes

International audienc

Antiretroviral therapy partially improves the abnormalities of dendritic cells and lymphoid and myeloid regulatory populations in recently infected HIV patients

This study aimed to evaluate the effects of antiretroviral therapy on plasmacytoid (pDC) and myeloid (mDC) dendritic cells as well as regulatory T (Treg) and myeloid-derived suppressor (MDSC) cells in HIVinfected patients. Forty-five HIV-infected patients (20 of them with detectable HIV load −10 recently infected and 10 chronically infected patients-, at baseline and after antiretroviral therapy, and 25 with undetectable viral loads) and 20 healthy controls were studied. The influence of HIV load, bacterial translocation (measured by 16S rDNA and lipopolysaccharide-binding protein) and immune activation markers (interleukin –IL- 6, soluble CD14, activated T cells) was analyzed. The absolute numbers and percentages of pDC and mDC were significantly increased in patients. Patients with detectable viral load exhibited increased intracellular expression of IL-12 by mDCs and interferon -IFN- α by pDCs. Activated population markers were elevated, and the proportion of Tregs was significantly higher in HIV-infected patients. The MDSC percentage was similar in patients and controls, but the intracellular expression of IL-10 was significantly higher in patients. The achievement of undetectable HIV load after therapy did not modify bacterial translocation parameters, but induce an increase in pDCs, mDCs and MDSCs only in recently infected patients. Our data support the importance of early antiretroviral therapy to preserve dendritic and regulatory cell function in HIV-infected individuals

Neisseria meningitidis Differentially Controls Host Cell Motility through PilC1 and PilC2 Components of Type IV Pili

Neisseria meningitidis is a strictly human pathogen that has two facets since asymptomatic carriage can unpredictably turn into fulminant forms of infection. Meningococcal pathogenesis relies on the ability of the bacteria to break host epithelial or endothelial cellular barriers. Highly restrictive, yet poorly understood, mechanisms allow meningococcal adhesion to cells of only human origin. Adhesion of encapsulated and virulent meningococci to human cells relies on the expression of bacterial type four pili (T4P) that trigger intense host cell signalling. Among the components of the meningococcal T4P, the concomitantly expressed PilC1 and PilC2 proteins regulate pili exposure at the bacterial surface, and until now, PilC1 was believed to be specifically responsible for T4P-mediated meningococcal adhesion to human cells. Contrary to previous reports, we show that, like PilC1, the meningococcal PilC2 component is capable of mediating adhesion to human ME180 epithelial cells, with cortical plaque formation and F-actin condensation. However, PilC1 and PilC2 promote different effects on infected cells. Cellular tracking analysis revealed that PilC1-expressing meningococci caused a severe reduction in the motility of infected cells, which was not the case when cells were infected with PilC2-expressing strains. The amount of both total and phosphorylated forms of EGFR was dramatically reduced in cells upon PilC1-mediated infection. In contrast, PilC2-mediated infection did not notably affect the EGFR pathway, and these specificities were shared among unrelated meningococcal strains. These results suggest that meningococci have evolved a highly discriminative tool for differential adhesion in specific microenvironments where different cell types are present. Moreover, the fine-tuning of cellular control through the combined action of two concomitantly expressed, but distinctly regulated, T4P-associated variants of the same molecule (i.e. PilC1 and PilC2) brings a new model to light for the analysis of the interplay between pathogenic bacteria and human host cells

Cell Invasion by Neisseria meningitidis Requires a Functional Interplay between the Focal Adhesion Kinase, Src and Cortactin

Entry of Neisseria meningitidis (the meningococcus) into human brain microvascular endothelial cells (HBMEC) is mediated by fibronectin or vitronectin bound to the surface protein Opc forming a bridge to the respective integrins. This interaction leads to cytoskeletal rearrangement and uptake of meningococci. In this study, we determined that the focal adhesion kinase (FAK), which directly associates with integrins, is involved in integrin-mediated internalization of N. meningitidis in HBMEC. Inhibition of FAK activity by the specific FAK inhibitor PF 573882 reduced Opc-mediated invasion of HBMEC more than 90%. Moreover, overexpression of FAK mutants that were either impaired in the kinase activity or were not capable of autophosphorylation or overexpression of the dominant-negative version of FAK (FRNK) blocked integrin-mediated internalization of N. meningitidis. Importantly, FAK-deficient fibroblasts were significantly less invaded by N. meningitidis. Furthermore, N. meningitidis induced tyrosine phosphorylation of several host proteins including the FAK/Src complex substrate cortactin. Inhibition of cortactin expression by siRNA silencing and mutation of critical amino acid residues within cortactin, that encompass Arp2/3 association and dynamin binding, significantly reduced meningococcal invasion into eukaryotic cells suggesting that both domains are critical for efficient uptake of N. meningitidis into eukaryotic cells. Together, these results indicate that N. meningitidis exploits the integrin signal pathway for its entry and that FAK mediates the transfer of signals from activated integrins to the cytoskeleton. A cooperative interplay between FAK, Src and cortactin then enables endocytosis of N. meningitidis into host cells

Sialyllactose in Viral Membrane Gangliosides Is a Novel Molecular Recognition Pattern for Mature Dendritic Cell Capture of HIV-1

An accessible sialyllactose moiety on viral membrane gangliosides is shown to be essential for HIV-1 uptake into mature dendritic cells, thereby promoting viral transfer and infection of bystander CD4+ T lymphocytes

A cinnamon-derived procyanidin type A compound inhibits hepatitis C virus cell entry

BACKGROUND AND AIMS: Chronic hepatitis C virus (HCV) infection is a major cause of liver disease worldwide. Although direct-acting antivirals can cure the large majority of treated patients, important limitations remain, including treatment failure and high costs precluding access to therapy in resource-limited settings. We report herein the anti-HCV effects of IND02, a procyanidin type A molecule, isolated and characterized from cinnamon. METHODS AND RESULTS: Using cellculture-derived HCV (HCVcc), HCV pseudoparticles (HCVpp), and subgenomic replicons, we demonstrated that IND02 markedly and dose-dependently inhibited HCV cell entry. Kinetic assays demonstrated that IND02 inhibits HCV entry most likely at a postbinding step. Experiments performed using primary human hepatocytes confirmed inhibition of HCV entry by IND02, demonstrating the functional impact in the most physiological cell-based system for studying HCV-host interactions. CONCLUSIONS: The natural compound IND02 exhibits potent HCV cell entry inhibition and provides a novel perspective for development of a low-cost antiviral for treatment of HCV infection