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Abundant cell surface receptors such as the epidermal growth factor receptor are not affected by the expression of Nef Madrid et al. Furthermore, at least two distinct subsets of cell surface receptors exist that are targeted by Nef via two independent, genetically separable mechanisms Mangasarian et al. Thus, discriminative mutations in Nef can completely abrogate down-regulation of one receptor subset, whereas levels of other receptors are still drastically reduced.

What governs this specificity and how these individual receptors are targeted by Nef is currently unknown. The Nef-induced down-regulation of CD4 and CCR5 independently and synergistically protected Nef-expressing target cells from HIV-1 superinfection due to an inhibited Env-mediated fusion of the viral with the target cell membrane Michel et al.

Here, we asked whether Nef proteins from human and simian immunodeficiency virus target multiple members of the family of CKRs or whether the Nef activity is specific for CKRs that can function as coreceptors for HIV entry. Because the modulation of CKR cell surface expression is a key regulatory mechanism for the signaling activity, we were particularly interested in mapping viral and cellular determinants to shed light on the strategy used by Nef to affect the cell surface expression of this receptor family.

To create the expression construct for Nef. The resulting pmRFP-N1 expression vector has intermediate sequences between the multicloning site and the fluorescent gene open reading frame identical to those of the pEGFP-N1 vector as has been confirmed by sequence analysis. Correct expression of RFP and Nef.

RFP was confirmed using confocal microscopy. Coexpression of Nef. GFP and Nef. The expression plasmid for CCR2 was kindly provided by Dr. Mark Goldsmith. GFP was kindly provided by Dr. Primary human CD4 T-cells were purified and activated as described previously Keppler et al. For biotinylated mAbs, streptavidin Alexa Fluor Invitrogen was used as secondary reagent.

Viral stocks were generated as described previously Schindler et al. Twenty-two hours after infection, cells were harvested, stained for cell surface-expressed CCR3, and subsequently fixed for 1. Analysis was performed by flow cytometry. SupT1 cells were directly seeded in well plates at a density of 1.

Interestingly, the dependence of the receptor down-regulation on the Nef concentration differed strikingly for CD4 and the CKRs. The CKR down-regulation followed a near logarithmic correlation, whereas CD4 down-regulation followed a near polynomial correlation Supplemental Figure 1. In contrast, CKR down-regulation required higher Nef expression levels and the minimal concentration of Nef required for efficient down-regulation varied for different receptors.

To our knowledge, Nef represents the first single stimulus that is able to simultaneously down-regulate eight different CKRs. Figure 1. One day after transfection, cells were stained with either receptor-specific mAbs or the anti-HA-tag mAb, and steady-state surface levels of human receptors were quantified by flow cytometry.

Identical R2 and R3 gates were applied for the statistical analyses of all panels shown in Figures 1 , 3 , and 4. Figure 2. We then examined whether the ability to down-modulate multiple members of the CKR family is a characteristic of Nef proteins from different primate lentiviruses. One day after transfection receptor levels were quantified by flow cytometry. The potency of the different alleles for reducing the cell surface levels of CD4, and, importantly, the CKRs, was fairly comparable.

Thus, the ability to down-modulate surface levels of human CKRs is conserved among lentiviral Nef proteins, and different CKRs apparently share a common determinant that is targeted by the viral protein. Figure 3. Twenty hours after transfection, steady-state cell surface levels of CKRs and CD4 were analyzed by flow cytometry after staining with either receptor-specific mAbs or the anti-HA-tag mAb. GFP or the indicated Nef mutants and analyzed 1 d later by flow cytometry Figure 4.

The Nef. In contrast, the potency of these mutant Nef proteins to down-modulate CD4 was well preserved. In summary, down-modulation of CC- and CXC-CKRs by Nef is genetically separable from CD4 down-modulation, suggesting that these activities are mediated by the interaction with distinct cellular pathways. Figure 4. Nef accelerates the endocytosis rate of several human cell surface receptors, and this, at least partially, contributes to the Nef-mediated reduction of steady-state surface levels of CD4, MHC-I, and CCR5 Aiken et al.

In particular at later time points, kinetic endocytosis assays can be affected by secondary effects of receptor recycling. Therefore, at this point we cannot exclude that Nef also targets CCR3 cell surface expression by inhibition of receptor recycling. Importantly, cells expressing low-to-medium levels of Nef. A significant fraction of Nef. GFP was also detected in this region and partially colocalized with all three receptors, as revealed in merged images Figure 5 A.

Accentuated CKR staining in the perinuclear region was occasionally seen also in GFP-transfected or untransfected control cells, suggesting that this perinuclear compartment may be involved also in the physiological life cycle of these CKRs.

We then sought to define this compartment more closely by performing colocalization studies with established markers for the trans-Golgi network TGN46; Figure 5 B and for recycling endosomes Rab GFP; Figure 5 C. Both of these compartment markers showed a considerable degree of colocalization with Nef and CKRs at the maximum resolution of this imaging technique. Furthermore, in cells expressing very high levels of Nef. GFP, the CKRs were detected neither on the cell surface nor in perinuclear compartments data not shown.

This observation is consistent with an accelerated Nef-induced receptor degradation as was previously seen for CCR5 in pulse-chase analyses Michel et al. In summary, Nef targets multiple CKRs to perinuclear compartments, where they accumulate and partially colocalize with the viral protein. Figure 5. GFP B , or Nef. GFP C. White asterisk indicates cells with perinuclear CKR accumulation. To this end, we analyzed different carboxy-terminal truncation and point mutants of the well-characterized CKR CCR5 that lack receptor elements critical for basal and ligand-induced internalization.

Figure 6. Identical amino acids are shaded in black, conserved residues are in dark gray, similar residues are in light gray, and unrelated amino acids in white. Thus, the CCR5 and CXCR4 carboxy termini, which harbor the classical and highly conserved motifs that are critical for basal and ligand-induced receptor desensitization and endocytosis, are dispensable for the Nef-mediated reduction of CKR surface exposure. Figure 7. Subsequently, cells were analyzed by flow cytometry.

Sequence alignment of the CKRs targeted by Nef highlights that in addition to the carboxy-terminal endocytosis motifs, only the DRY motif in the second intracellular loop, which plays an important role in GPCR activation and signaling via heterotrimeric G proteins Scheer et al. Figure 8. In contrast, CXCL12 down-regulated both the wild-type receptor and the NAA mutant with comparable efficiency Figure 8 C , demonstrating a preserved capacity of the CXCR4NAA mutant for ligand-induced internalization and excluding a gross deficiency of the integrity and membrane localization of this receptor mutant.

Figure 9. Asterisks indicate the time of ligand addition. Next, we investigated the role of the DRY motif integrity for the Nef-induced CKR down-regulation with respect to its role in receptor signaling in more detail.

Both of these CKR mutant proteins were down-regulated by Nef with efficiencies comparable with the wild-type receptors Figure Figure Cell surface levels of mutant and wild-type CKRs were analyzed in principle as described in the legend to Figure 7. Nef apparently uses a nonclassical, yet general pathway to regulate the surface exposure of CKRs. This pathway does not require carboxy-terminal CKR motifs necessary for agonist-driven receptor endocytosis, but, at least for CXCR4, depends on the DRY box motif in the second intracellular loop.

The versatile functions of CKRs in leukocyte biology require a precise regulation of signal initiation and subsequent desensitization after ligand engagement. The modulation of the cell surface density is a key mechanism regulating the signaling activity of all CKRs Neel et al. The fact that all of these diverse CKRs were targeted with comparable efficacy by the identical motifs in Nef from HIV-1 SF2 suggests that a universal, possibly indirect mechanism may be used by the viral protein.

Interestingly, Nef uses the identical motifs to reduce the surface expression of structurally unrelated MHC-I molecules. One model of the Nef-induced receptor modulation postulates that the viral protein acts via a direct physical interaction with the respective receptor Peterlin and Trono, In line with the scarcity of reported interactions, we did not find evidence for a physical association of Nef and CCR5 in coimmunoprecipitation studies from CHO cells data not shown.

In light of the rapidly growing list of only distantly related receptor molecules, the surface exposure of which is modulated by Nef, a more general mode of action, that may not necessarily require physical interaction, seems likely. Recently, a generalized alteration of endocytic vesicle trafficking induced by Nef was proposed as a mechanism for affecting cell surface receptors, including the transferrin receptor Madrid et al. In line with such distinct sites of Nef action, we found markedly different degrees of concentration dependence for down-regulation of CD4 and CKRs Figure 1 and Supplemental Figure 1.

Also relevant in this context, we have recently compared the expression of HIV-1 Nef after transfection of the identical Nef expression plasmids, that were used in the current study, and HIV-1 infection and found comparable expression levels of the viral protein Keppler et al. Our kinetic endocytosis assays and localization studies revealed that Nef only moderately accelerated the rate of CKR endocytosis. GFP expression plasmids data not shown , it seems likely that mechanisms other than accelerated endocytosis of surface-exposed receptors contribute to this Nef-mediated phenotype.

Conceivably, the sum of such interferences may result in the net reduction of cell surface CKR levels and the pronounced perinuclear accumulation observed at steady state in Nef-expressing cells. Irrespective of the sorting mechanism used, our previous results obtained for CCR5 Michel et al. It is conceivable that Nef acts at the early endosomal compartment Madrid et al.

Nef possibly perturbs the rapid recycling of CKRs to the cell surface and reroutes the receptors to a perinuclear compartment. This compartment may be related to the slow recycling compartment that was found to be involved in normal trafficking of some CKRs Neel et al.

In our opinion the resolution of confocal microscopy does not allow a clear distinction between these and other closely adjacent perinuclear compartments. Our data show that lentiviral Nef proteins have evolved a general strategy to affect the cell surface levels of CKRs.

The existence of a mechanism that targets such a broad class of cell surface receptors may reflect the need of HIV to down-modulate both of the divergent major entry coreceptors CCR5 and CXCR4 to efficiently protect productively infected cells from superinfection Michel et al. However, the newly found Nef activity of down-regulation of at least eight different CKRs is not restricted to those receptors that function as HIV coreceptors. The reduced CKR expression on these cells may disturb the coordinated action of host immune responses against virus-infected cells Esche et al.

At present, there is only limited knowledge about the regulation of the internalization rate and intracellular trafficking of individual CKRs under physiological conditions in the absence or presence of ligand. In general, parameters known to influence receptor endocytosis include the type and concentration of ligand, composition of the CKR cytoplasmic tail, receptor phosphorylation status, and abundance of endocytosis-associated adaptor molecules in the cytoplasm Neel et al.

The mechanism by which lentiviral Nef proteins reduce CKR cell surface exposure differs by several criteria from known pathways used by individual CKRs for internalization and intracellular trafficking. This contrasts the situation under physiological conditions, during which chemokine ligands are the main trigger for CKR cell surface level reduction that is primarily mediated by an accelerated clathrin-mediated receptor endocytosis. However, this alternative pathway seems to be restricted to certain cell types and the evaluation of its importance in vivo has so far not been possible Signoret et al.

Second, classical endocytosis motifs in the CKR cytoplasmic tail are not required for the Nef-mediated receptor down-modulation. Leading in changing times for our Clients, our People and Society. All rights reserved. Nous rendons possible chaque unique. Nous unique. Rendez-vous sur www. Il fait partie des jeunes loups de la politique, au parcours pour le moins intense.

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She is also a member of the Coordination Committee of the Ministry of the Economy, which she joined in as Deputy Chief of Staff and Diplomatic Advisor of the former Deputy Prime Minister, following her year career as a Luxembourg diplomat. She also chairs the Luxembourg Nation Branding Committee. Bogdan Banice est membre du Paperjam Club depuis Karin Basenach studied law at the University of Trier state examinations in law in and with a specialization in European law.

She worked several years as a lawyer in Germany. In , she became a certified Mediator and Coach. Since , Ms. Basenach is a member of Team Europe Luxemburg. Basenach gives on a regular basis presentations on European Consumer Law and moderates conferences. She has the German nationality as well as Luxemburg's nationality. En septembre , il devient le directeur Entrepreneurship de la Chambre de commerce.

In , he combined this function with that of Head of Capital Markets for Belux. Maurice Bauer is a municipal councillor of the City of Luxembourg since He is Chairman of the Board of Directors of the Foundation "Maison de la Porte Ouverte", an organization that takes care of abused and disadvantaged children and women as well as of immigrants.

During his studies, he worked as a journalist at the European Parliament and at the Council of Europe. Depuis , il est membre de la direction. Membre-fondateur de l'a. Etant conseiller communal de Wellenstein, il s'est investi en faveur de la fusion des communes de Burmerange, Schengen et Wellenstein.

En juin , Oryon change de nom pour devenir koba. Luc Biever, 48, holds a degree in Applied Geography from the University of Trier and joined ILReS Market Research as a researcher on 1 May , before being promoted to senior researcher in and director of studies in Since he has been managing director of the company. He is a Luxembourg national and was educated in France and in the UK. He re-joined the firm from a big four organization, where he was an international tax partner.

With over 30 years of tax experience in the international markets of London, Tokyo and Sao Paulo, Willem specializes in cross border tax issues of businesses, funds as well as individuals, often involving one or more of the Americas jurisdictions. He has a large experience in tax, vat, accounting and audit as well as corporate finance and advisory since more than twenty-five years.

He has a significant track record in wealth structuring, investment funds and other Private Equity vehicles, with a special focus on real estate. Romain is a Board member of a selection of alternative investment funds. Romain is active in charities and an international service club, as an honorary life member. Fatah acts as a director of several specialised investments funds and non-regulated vehicles.

Il dispose d'une formation en relations internationales, en philosophie et en management. While he focuses on the strategy of the firm, he also heads the corporate practice group and advises clients on corporate, banking, reinsurance, securitisation, and capital markets. His constant concern for quality is much appreciated by his clients, among whom are leading international companies and financial institutions.

Freddy Brausch is a member of the Luxembourg bar. He has been a partner in Linklaters Luxembourg's investment management group since and served as the office's Managing Partner for many years. He has been ranked Band 1 by Chambers consistently. He is acknowledged by clients for his "considerable industry knowledge". Freddy is sought after for advice on the evolution of the European and Luxembourg fund sector and regularly speaks at conferences in Europe, Asia and the US.

He serves as an independent director on the Boards of several fund complexes. He presented his credentials to the Grand Duke of Luxembourg on 25th September With over 12 years experience in the Luxembourg real estate Industry, Carole has developed strong, personal relationships during her successful career. Her knowledge of the Luxembourg real estate market is keen and her desire to serve her clients is unmatched. Her professional experience includes a position as Account Manager with a large local bank followed by a position as Tax Manager with one of the big five.

Besides her Management skills, Carole presents Tax, Legal and Financial skills enabling her to guide her clients to the right decision. Prior to incorporating the firm, Oscar Casas held the role of manager, head of legal and compliance officer at a Luxembourg Management Company and AIFM, as well as member and shareholder of a law firm focused in the legal advisory of financial sector entities. As a tireless connector, Pedro has been involved at board level in Junior Chamber International an Indian Business Chamber Luxembourg and is currently a board member of the International School of Luxembourg and a mentor with the Incubator of the University of Luxembourg.

After a 2 decades career in banking and with 25 years experience in addressing audiences, Pedro Castilho aims now at helping people to be successful in speaking in public. He is frequently appointed by the court as receiver of unclaimed estates and non-commercial associations. Eric started his career as a fund accountant with PFPC. In , he joined Mercuria Services subsequently Mercuria Management Company , a prominent Luxembourg third party management company, where he was responsible for Business Analysis and Risk Management before taking up the role of General Manager.

He is also a member of various professional committees. For more than 20 years, Thierry has specialised in VAT, customs, excise duties, international trade matters, real estate and in transfer pricing matters. He also advises clients on real estate transactions.

Thierry is frequently asked to speak at seminars on VAT and customs-related matters. Son leitmotiv? Previously he was a Business Executive for Asset Servicing, and member of the management committee of the Brussels Branch. Prior to joining BNY Mellon, he worked for a Continental European fund manager, running 3rd party fund distribution as well as operations for their Luxembourg management company.

He started his career in as a fund accountant in Luxembourg. Carlos Cipollitti joined Goodyear in and has held a variety of technical and managerial roles in Latin and North America, Europe and Asia Pacific. Cipollitti is American and grew up in Venezuela. He is married and father of three children. Il rejoint Luxembourg en et s'oriente alors vers le conseil en informatique. L'exigence qualitative de la production architecturale et urbanistique devient une marque reconnue de l'Atelier.

He has played a key role in the repositioning of the life insurance company on the segment of the Private Wealth Insurance Solutions and in the opening of the distribution network. Van Breda. In his home country of Australia, Warrick Cramer built numerous businesses from the ground-up in the automotive, mobile payment, and advertising industries.

His biggest entrepreneurial success was an app that captured securing mobile payments which went on to be implemented worldwide. His experience and passion for innovation and business development ultimately brought him to Vodafone, where he devotes his talent and entrepreneurial mind-set to revamping innovation at the heart of Vodafone's Supply Chain.

He faced many hurdles before finding success. He went through the journey of expanding his business in other markets all on his own. Inspired by his personal experience of lack of support and guidance as an entrepreneur, led him to form Tomorrow Street, an innovation centre in partnership between Vodafone and Technoport.

Guy Daleiden graduated in History and German linguistics and literature at the University of Freiburg i. He started his professional career as a civil servant in , when he joined the Prime Minister's office. He has been the managing director of Film Fund Luxembourg since , where he is in charge of promoting the audiovisual production policy of the Luxembourg government.

In this capacity, he is responsible for implementing the government's audiovisual production support policy, assists ministers in the drafting of regulations and legislation and in developing international co-production agreements. He represents Luxembourg in a range of European and international audiovisual initiatives. Voir fiche page Claire-Marie Darnand combines her practical and academic expertise in assisting clients in achieving their legal and commercial goals.

Claire-Marie is primarily engaged in business transactions and corporate law. In such matters, she handles mergers and acquisitions, reorganisations, restructurings, joint ventures and corporate real estate. Furthermore, she advises clients on private equity matters such as acquisition structuring. Un challenge enthousiasmant pour cet homme qui envisage le futur avec optimisme.

In September of , in a shark market where some quit and others fight with no rules, he decide to open CUBE LiFT, an original Luxembourgish Elevator Company, a company that came to break the routine and make revive the Craftsman spirit. Lucas et M. Petit ; rejoints, en , par A. Pierre Delandmeter started his unpaid volunteer career in international humanitarian assistance when joining Handicap International in its inception in Luxembourg in He then became member of the Board and Chairman in Avant de reprendre la direction du groupe BIL, M.

Until February his commitment was based on a mandate and volunteer basis. Luxembourgish born, graduated at the University Louis Pasteur Strasbourg , he likes promoting Luxembourg as a great place to live and to do business. Guillaume Desjonqueres is chief executive officer of Syncordis.

Guillaume manages corporate direction and strategy, facilitating company activities in solution architecture and design, consulting, sales, partnerships, as well as support, client relationship and project direction. Guillaume has two masters in International Business and Economics. Throughout his career, Guillaume has built a strong and reliable reputation in the banking software implementation industry.

His deep knowledge, expertise and vision, has earned him a solid reputation as well as the trust of numerous senior executives and transformation project sponsors. Di Maulo has over twenty five years of experience in the stainless steel industry, having held a number of positions in the controlling, purchasing, logistics and commercial areas and has been CEO of different units of the Group.

Previously, Mr. Prior to this function Mr. The joint venture of Sony and Ericsson led her to its Headquarter in London, where she filled different international roles, such as Head of Global Sponsorship Marketing. Before acquiring Bizart in , Danielle was Board Director of the Parisian office, of the internationally renowned advertising agency Iris Nation.

Colette Dierick has a very long and strong relationship with ING, having been recruited in Brussels in First as general manager Retail Distribution and later as Managing Director, she was the driving force for integrating the digital channels as sales channels. Olivier Dorier has over 20 years' experience in corporate services and was a founding partner of MAS International.

He has extensive experience in incorporation, management, accounting and liquidation of SPVs and acts as a board member in Luxembourg SPVs for large multinational groups. Oliver Dorier also has experience in private equity and real estate and occupies a position as a board member in various European countries including Luxembourg, Belgium, Germany, France and Spain.

From to , Olivier Dorier worked as head of accounting for a Dutch corporate service provider in Luxembourg. He is bilingual in French and English. Voir fiche page Diogo Duarte de Oliveira advises investment firms and multinational companies on their fund-raising structures, crossborder holding, financing, IP licensing and supply chain strategies. Diogo started his career in Portugal and has built his international tax experience in the Netherlands, Mexico, and Luxembourg, where he has been practising since He often publishes technical articles in renowned international tax magazines.

In addition, Diogo regularly acts as a guest speaker or panelist around the world. Annie has extensive experience in handling complex matters involving pension benefits, social security aspects and corporate restructuring involving employment law as well as implementing strategies in the best interest of the clients during legal proceedings.

In addition, Annie has significant experience of handling commercial litigation as well as employment litigation for both claimants and defendants. She has also been involved in transactional and arbitration work. Annie is qualified to practice in both Luxembourg and France.

She is a member of the Luxembourg Bar. Jacques Elvinger practises commercial, company, banking and finance law. He is a lecturer at the University of Luxembourg and holds courses on the examinations for admission to the Luxembourg Bar. Jean Elia has 24 years of experience in Insurance, out of which 12 as CEO of leading life insurance companies. Specialised in strategy and leadership, he has advised several insurance companies and conducted structural changes and Bancassurance model implementations in the Middle East and Europe.

He was admitted to the Luxembourg Bar in After practicing for 16 years in the largest Luxembourg independent law firm, including 7 years as a partner, he joined Hogan Lovells as corporate partner of the Luxembourg office in Ambassador J. Before becoming Ambassador, he served as a distinguished attorney, author and public servant a variety roles at the federal, state and local levels of government.

Ambassador Evans has coauthored eight books, two syndicated columns, and numerous programs and seminars on topics ranging from professional ethics to climate change. He appeared regularly on national cable news networks on current political events. For his work and service, he has received numerous awards and recognitions across the United States.

Notions antagonistes? He then had the opportunity to take the entrepreneurial route, with the creation and expansion of an electronic money institution, until resale in After beginning his career at Citigroup Dublin, he joined Vontobel Management, where his responsibilities as director and executive manager included heading both client services and management company teams.

He joined Notz Stucki in He specialises in mergers and acquisitions, securities and stock exchange-related work, takeovers and joint ventures. He has 30 years of experience advising clients across all sectors, including financial institutions, private equity, real estate, insurance, energy, communications, media and technology. Marc is considered as one of the market's top corporate lawyers.

Annick Felten est membre de la direction du Commissariat aux assurances depuis He graduated in commercial and financial sciences with a specialization in chartered accounting and has extensive experience working in ICT and Government related environments in both the operational and regulatory domains. In her role, Cristina works closely with the fund industry innovators and promotes adoption of digital client service delivery models. Prior to this, Cristina was the Chief Administrative Officer since responsible for internal governance, business control enhancement programs and coordination of strategic initiatives.

The same year, she was also appointed to the State Street Bank Luxembourg management board. Cristina has been working for State Street in Luxembourg since and has held a variety of management positions. Noel entered financial services in after a year military career. Noel led a team that developed the company into Schroders' largest operations centre outside of London. Noel was appointed Schroders' global head of fund services in and chief operations officer of the product division in Voir fiche page Claude Feyereisen has a total of 16 years in the legal profession in Luxembourg.

He advises local and international clients on all aspects of corporate and commercial law. Elle est aussi une des membres du collectif citoyen 5vir Emmanuel Fleig a rejoint le conseil de presse en septembre Reich choisit de retourner en Suisse pour raisons personnelles.

Christine Fornaroli is equally familiar with the executive world and investments as she is with starting a new life in unfamiliar territory. A seasoned expat, she knows how to land on her feet. Fluently at ease in 6 languages, she has a deep, personal understanding of crosscultural issues. Her passion to help people adjust and surmount difficult challenges along with her extensive experience and network are a mighty force.

High-level executives and families with full schedules and high demands find that Christine is the secret ingredient for efficient, discreet, seamless integration into their new lives abroad. Christine is a Certified Boat Director currently serving on the board of French and Luxembourgish companies. In March , she becomes Country Manager Luxembourg. Partir, revenir After 18 years, the company has around people, several activities, splitted in 3 countries.

Starting his career at Fortis Bank Luxembourg as Relationship Manager before taking the opportunity to join BNP Paribas Group in the investment fund industry and securitization department. His senior experience in managing and developing investment strategies and products allowed the company to wider the service range it could offer to its international clients.

Depuis , il dirige l'Orchestre Philarmonique du Luxembourg. Partner at Linklaters Luxembourg since and head of the Capital markets and Banking group. He specialises in banking matters credit and taking of security , restructuring and insolvency, structured finance tax-based and fundlinked products and asset finance.

He is also in charge of the overall co-ordination of the real estate offering for the Luxembourg office. En , il prend la direction de Logica devenue CGI en Marc Gerges started his career working as a free-lance journalist in France and Luxembourg. Taking over the Corporate Communication department he notably developed an internal communication approach and initiated the Rebranding project in line with the Building a New Airline strategy.

In , he gave his career a new breathe when he became Partner at Maison Moderne. Appointed as Editorial Director, he was in charge of managing all print and digital media. Seeking for new challenges, he founded his own agency, specializing in strategic communication consulting in In , Marc Gerges returned to LuxairGroup as a member of the Executive Committee and took over the communication and marketing departments.

Robert Goebbels a la retraite active! Prior to Internaxx, he worked as Product Manager for Mars in Germany, and was responsible for new product developments. Il est, en outre, un des membres fondateurs du collectif 5vir Voir fiche page Renaud Graas advises clients on a wide range of alternative funds matters.

Renaud has gained thorough experience in fund review and fund formation matters. In addition, Renaud advises clients regularly on insurance regulatory matters. He has worked for more than a decade in the Luxembourg funds practice of a Magic Circle firm. Renaud joined the Luxembourg office of Stibbe in He is a regular guest speaker or panellist in conferences and is the author of various publications on the subjects of investment funds and related regulatory topics.

Initially working in the Global Custody department he transferred to Luxembourg in After a brief spell in Frankfurt in Jon returned to the UK later in to work in Relationship Management servicing clients domiciled in Ireland. He returned to Luxembourg in July and continues to be based here. Dans son temps libre, il pratique sa passion : les sports de glisse.

Son restaurant obtient un macaron au guide Michelin en In , Bert Habets was awarded 'Most influential broadcast personality of the year ' in the Netherlands. Mario Grotz started his career working for the Chamber of Commerce and the Chamber of Craft, where he acted as an advisor to SME in areas concerning business creation and business management. From he was appointed Head of Directorate for Infrastructures and Technology.

Since he is the General Director for Research, Intellectual Property and New Technologies, responsible for the development of the technology based sectors in Luxembourg: cleantech sector, biotech sector and ICT sector including the space sector. He also represents the State of Luxembourg in different boards of private companies. Xavier focuses on cross-border banking and finance work, including funds finance, secured lending, leveraged and acquisition finance and asset-backed finance, as well as insolvency related work.

He also deals with global restructurings and assists insurance sector players. He regularly advises banks and other financial institutions, private equity houses, real estate investment structures and other international companies in these fields. He worked for Vodafone for 10 years during which he held various senior finance positions.

He also served as a director on the boards of all Vodafone Luxembourg companies. Prior to this, Olivier worked as a Senior Advisor for a Big Four firm providing domiciliation and accounting services as well as a Financial Controller for a UK multinational company.

Olivier holds a postgraduate university degree in Finance as well as a Bachelor of Science in Business Administration. He specialises in corporate projects, advising multinational and domestic companies and High-Net-Worth Individuals.

He has been a member of the Luxembourg Bar since and served as Chair of the Luxembourg Bar Council from to Sharing his knowledge and professional experience is very important to Guy. Guy started his professional career in the finance department of Arbed, now part of ArcelorMittal, the global steel company headquartered in Luxembourg, working on long-term debt and export financing. Christian has a wealth of experience in the financial services industry having held a number of senior roles in Luxembourg, Hong Kong and China.

He also held senior management roles in Luxembourg office before moving to Asia in and had worked with Private Equity, Corporate and Private Clients. Furthermore, Mr Hemmer has also been an active member of various financial organisations. In , Mr. Hemmer sought new challenges and joined LuxairGroup, where he currently holds the position of Vice-President of Human Resources. He was a guest professor in Beijing, in Paris and in Georgetown, and a scholar-in-residence at the New York University.

He served as a part-time judge at the Court of Appeal of Karlsruhe. Professor Hess often acts as an advisor to some European institutions and national governments. Nico Hoffeld, Managing Partner, joined MindForest in July as a managing partner and is in charge of client and stakeholder communications and MindForest business development Nico has specialised in internal communication audits and holds ample experience within the area of project support.

VCM focussed on projects within the field of new technologies and life science. From to Nico was in charge of MbS, a communicationconsulting agency that won innumerable international awards. MbS was the market leader in the 90s and one of the most respected consulting agencies in the whole Saar-Lor-Lux area.

Nico graduated in human science. She specialises in the areas of commercial law negotiation of contracts , litigation, arbitration, real estate and IP law. Christiane Hoffmann is the founding manager of lilith project, aiming to provide groundbreaking Human Resource solutions that can benefit companies and institutions in all sectors. In that position, he successfully led the re-engineering of the UBS governance model in Germany, increased operational and front-line efficiency across all business lines, introduced new technology and steered one of the biggest IT and operational projects, positioning the company for sustainable growth.

Manou Hoss is responsible for the overall management strategy, including people, knowledge management and finance. She is a member of the Board of the Luxembourg Red Cross. He has built up a vast international experience in Asia and Europe and gained extensive executive management experience. Dr Hoyer holds a PhD economics from Cologne University where he also started his career, as senior research assistant then as associate lecturer, before becoming Director of Economics and Information Carl Duisberg Society in Il est membre effectif du Conseil Economique et Social.

Mais pas question pour autant, pour lui, de se reposer sur ses lauriers. After 20 years of creating a multitude of businesses and non-profit organizations, Marco Houwen focuses today on implementing purpose-driven, self-managed leadership in organizations. Marco co-authored a book," So you've got a DAO " on distributed and connected leadership, helping de-centralized organizations to put in place the mindset necessary to achieve excellence in their global organizations.

Marco Houwen is passionate about human excellence and always strives to become a better leader and more important, to empower others to accept their greatness as a leader. Nicolas holds a Bachelor degree in Economics and speaks fluently English and French.

Martin's aviation career spans 30 years and covers virtually every aspect of the airline business from sales and marketing to product, ground-handling, operations and maintenance. Voir fiche page Steve Jacoby co-heads the Luxembourg Banking, Finance and Capital Markets practice and handles acquisition finance, bank lending, securitisation, capital markets, regulatory, derivatives, general banking law including litigation , corporate law and insolvency matters.

He will assume the role of Managing Partner of the Luxembourg office as from May He is a regular contributor to legal journals and a member of various advisory committees on financial law questions within Luxembourg public institutions and professional organisations. Renaud Jamar y occupe la fonction de CEO. She also assists companies in many areas of business and commerce, including business authorisations and commercial contracts. Il occupera cette fonction jusque fin Guill Kaempff joined the family company Kaempff-Kohler, founded in by his grand parents, in upon his graduation from Centre Universitaire in Luxembourg.

He is the president of the Luxembourg City Retail organisation since and a member of the Rotary Club Luxembourg-Horizon since Guill Kaempff also serves the Luxembourg Russian Business Chamber as a member of the board since He enjoys travelling, cycling and swimming.

Together with his brother Christian Kaempff, he is constantly improving his business, deli and restaurant, and is looking forward to leading the company to its th birthday. Apollo Strategists accompagne des entreprises internationales et locales. Il devient ensuite CEO en In , Koedinger founded the start-up Lemonland Media Lab, a new platform to explore and celebrate what the world of publishing media does best. Specialized in private equity, he is the founder of the EY Private Equity practice which he led until He is a member of the EY Regional European leadership team.

Alain Kinsch is also member of the Luxembourg State Council. En , il introduit avec Aston Martin une nouvelle marque automobile au Luxembourg. Il assume aussi, entre et , le mandat de ministre des Sports. In his role, Serge Krancenblum ensures that the organization has the capacity and clarity to deliver on its global mandate: client service excellence, sustainable growth, and efficiency, across all of its offerings. Throughout his career, Serge Krancenblum has deepened his expertise in developing and managing transnational solutions for institutional investors, multinational corporations and entrepreneurial families.

He is recognized for his leadership throughout the financial industry, and is frequently invited to speak at local, national and international events. He also sits as an Independent Director on the boards of several real estate and private equity funds, as well as on those of selected listed and private companies.

He has spent more than 23 years in the financial sector, 21 thereof in the Luxembourg investment fund industry. He also heads the corporate and capital markets practices. He acts for banks and other financial institutions on regulatory, banking, finance, capital markets and insurance matters. His whole professional career has been devoted to the global fund and asset management industry. Claude sits on the board of various international asset management groups as well as their fund ranges in Luxembourg.

From to , he was chairman of the Association of the Luxembourg Fund Industry. In addition, he is a lecturer in fund law at the University of Luxembourg. He heads up a team of about professionals. He specialises in international litigation, in particular in the fields of asset tracing, white-collar crime and corporate disputes. He has been a member of the Luxembourg Bar since He is approved as mediator at the Civil and Commercial Mediation Centre.

Kremer is the acting Chairman of the Luxembourg Bar Association until , after serving as Vice-Chairman since Martin Lagneau started his career in the field of humanitarian assistance with Handicap International in He rised through the echelons and presently occupies the function of Executive Vice-President Tour Operating and Sales.

He lives in Luxembourg and has two children, a boy and a girl. In his rare free time, he likes to relax with wife and family. With his professional background in banking and trading, Michael brings common sense operational efficiency to boardrooms. He also has distinctive experience in risk management and compliance oversight experience, as well as in structuring.

Michael is fluent in German, English, Luxembourgish and French. Throughout his career, Arnaud Lambert has been at the confluence of management, IT and logistics. From to , he rose through the ranks of the company, to become CEO in At CHAMP, Arnaud has played leading roles in developing the portfolio, in expanding the geographical footprint of the development teams, and in strengthening the customer service and operations model.

Sandra joined the company in February Her other responsibilities related to audit quality, organisation of audit methodology trainings and implementation of a new audit documentation tool. Isabelle Lebbe is a Partner in the Investment Management practice where she specialises in a wide range of investment funds with a focus on regulated funds and management entities.

Isabelle also works with her colleagues in the litigation team on regulatory complaints and judicial proceedings involving regulated funds or their service providers. She is in charge of diversity and inclusion within the firm. She also heads Arendt Institute, the training division of the firm. Isabelle is a regular conference speaker. She participates to a number of committees established by the Association of the Luxembourg Fund Industry and the regulatory authority of the financial sector in Luxembourg.

Michael Leidinger, Dipl. He joined the company in as Technical Director. He decided to continue his career in Account Management at Omnis Sofitec where his main focus was on backup and storage technologies oriented sales. In , he joined System Solutions Luxembourg and held the same function while dealing with large accounts in banking and institutional areas until Pierre-Michel Lemaire is very passionate about highend technologies and their impact on society evolution, human behavior and business opportunities.

His hobbies include design, reading and martial sports. He speaks French, English and German. Le renouvellement de M. He started his career at PricewaterhouseCoopers in , as Senior Auditor. Il est admis au Barreau de Paris depuis et au Barreau de Luxembourg depuis He is first and foremost an entrepreneur, just like his family before him.

According to Xavier, only companies that offer truly innovative tools and services can hope for success tomorrow. He is also responsible for a portfolio of Asset Management clients. Steven Libby has more than 20 years of experience with internal control evaluations, including in the areas of securities services, transfer agency, fund tax reporting, and governance matters, among others.

En , il rejoint Natixis Assurances. He has more than 20 years of experience in the fund industry. He also serves as the Global Fund Distribution Leader. He divides his time between our Luxembourg and Hong Kong offices. He specialises in corporate law, corporate finance, private equity, mergers and acquisitions, real estate, securities regulations and banking and finance matters. Thierry has represented clients in numerous cross-border transactions, either public and private, including major public takeover bids and listings of securities on Euronext, Nasdaq, the Luxembourg Stock Exchange, the London Stock Exchange and the Hong Kong Stock Exchange.

Thierry is a member of the Brussels and Luxembourg Bars and is registered as a foreign lawyer in Hong Kong. He is a member of the Luxembourg Bar since and a top tier litigator specializing in complex court cases and behind-the-scenes negotiations. He is regularly involved in commercial cross-border matters and is very active in banking litigation and construction litigation cases, as well as real estate and employment matters.

Laurent Loschetter founded his first company dsl back in at the age of Since then this company has grown to become a key component for IT infrastructure in Luxembourg. Amidst various other activities, in he created the concert promotion company den Atelier. In september , the council of government of Luxembourg approved the proposal of Prime Minister Xavier Bettel and appointed him as chairman of the board of directors of the radio ,7. Bretz et S. Dell et M.

She focused on ensuring optimal operational set up, cost efficiency, and client centric solutions with a focus on control and governance. Since then, Victor Buck Services has expanded internationally and supports clients from Singapore, Hong Kong, the UK, Sydney and soon Taiwan, with a special attention to their digital transformation and security challenges. Edith also serves on various boards such as Seqvoia, Fedil ICT and I-HUB and advisory boards with specific focus on data protection, cyber security, digital transformation and more.

He is known in the fund industry for his in-depth knowledge of the asset management value chain. Most recently he co-founded Inreg. Mario is a regular speaker at industry conferences and events as well as an experienced teacher. Mario is married with two children.

Sharon March, an established expert on ethics, is founder of March Senior Consult-Ethics: specialised in pure applied ethics advisory for the board level and organisation wide. She teaches ethics and finance at universities; assesses ethical investments, policies, and operations. She has worked in treasury, private banking and government consulting. She is active on boards, uniquely uniting ethical and financial choices, and an accredited mentor at the Chamber of Commerce.

En novembre , le groupe AccorHotels acquiert le groupe John Paul. John Marshall joined the Foreign and Commonwealth Office in Frank Mausen advises bank, corporate, institutional, supranational and sovereign issuers on debt and equity transactions and structured finance transactions including securitisation, structured products, covered bonds, IPOs, placements, and buy-backs of securities, exchange offers and listing applications.

Laurent advises banks, professionals of the financial sector, re- insurance companies, listed and non-listed companies and securitization undertakings on regulatory issues such as banking, finance, capital markets and re- insurance matters.

His practice includes cross-border banking and capital markets transactions including issues of debt and equity securities such as high-yield bonds issues and IPOs, de- listings, takeovers, exchange offers and buy backs , structured finance, acquisition finance, restructuring and insolvency as well as re- insurance transactions.

Laurent regularly chairs and organizes conferences and seminars. He is also regularly invited by banks for internal training sessions and for internal regulatory assessment purposes. La cuisine lui offre tous les jours une occasion de communion et de partage avec les autres. She was admitted to practice as a solicitor in Ireland in She also qualified as a tax consultant with the Irish Taxation Institute in Active in the field of life insurance and pension funds since in Luxembourg, he has participated to the development of the place of Luxembourg in these sectors as Deputy Manager at Swiss Life, Actuary and Consultant at PWC and Managing Director of La Mondiale before creating Hepta Consult, specialized in independent insurance and actuarial services.

In he was the co-founder of Pack Assurance Management, the first outsourcing company agreed as PSA in Luxembourg for offering regulated services in the life insurance daily management, solvency, compliance and reporting. Since many years he is an expert recognized by the Luxembourg Courts for the valuation of long term assurance indemnities. Nous vous proposons les plus belles demeures du pays en accord avec votre style de vie.

Marc also advises fund managers on all applicable regulatory matters. He has broad experience in handling corporate and secured financing matters. He worked for several years in the Luxembourg office of a leading international law firm, as well as in the New York and London offices of a major US firm.

He is a member of the Luxembourg and New York Bars. Bady Minck works as an artist, filmmaker and producer in Vienna and Luxembourg. Lakshmi N Mittal is the chairman and chief executive officer of ArcelorMittal. Mittal is a philanthropist and a member of various boards, including Goldman Sachs. He is also a member of the board of trustees of Cleveland Clinic and a member of the advisory Council of Harvard University. In addition to forcing the pace of consolidation in the steel industry, he has also championed the development of integrated mini-mills and the use of directreduce iron as a scrap substitute for steelmaking.

Bernard Moreau, originally from Antwerp, has been integrated into the Luxembourg business community since Initially active in various commercial roles supplying services to the Luxembourg financial sector, Bernard has co-founded Lab Luxembourg in and is currently its CEO.

Lab Luxembourg offers bespoke Information Lifecycle Management Solutions, a unique transversal platform for document and data management. Bernard Moreau is active in various associations, a keen traveller and a firm believer in hard work combined with fun. He is the Managing Partner of the firm. Educated at the Universities of Strasbourg and Vienna, he began his career at an Austrian bank and has acted as an advisor to local and international clients in all aspects of their daily business activities.

Michel has extensive experience in banking and finance advising domestic and foreign banks, insurance companies and other professionals of the financial sector on the whole spectrum of regulatory compliance issues. He is a renowned litigator and employment lawyer and an active member of many associations and is consistently recommended in the main Legal Directories. Prior to his current role, Aditya was chief financial officer of ArcelorMittal with responsibility for Flat Carbon Europe, investor relations and communications.

Son parcours est exemplaire. Le restaurant a fait peau neuve en novembre Peter heads the Luxembourg transfer pricing team and is also active in the German and Eastern European desks. He regularly writes and speaks on tax developments in Luxembourg. Laurent Moscetti has been involved in several large scale, crossborder business transformations for major private banks in Europe and post-merger harmonisation programs.

Frederic Mouchel is a Managing Director at J. Morgan Chase. Morgan Bank Luxembourg S. Prior to taking this role in Luxembourg, Frederic was J. Over the last 20 years, Frederic had held various management roles in the Firm Treasury function in the Investment Bank and then in Finance or Corporate based first in Paris and since in London.

Before transferring to the front office and become Branch Treasurer and Head of Repo for Paris in , he held various positions mostly as a financial controller for Market activities. He joined the firm in He has been a member of both the Luxembourg and Brussels Bar since He is a member of various working committees at the Commission de Surveillance du Secteur Financier CSSF , the regulatory authority of the financial sector in Luxembourg and acts as a non-executive board member in numerous companies.

En elle rejoint l'entreprise familiale les boulangeries Fischer, dont elle est aujourd'hui le dirigeant. Her work has been presented at numerous leading international conferences and has been published in various top ranked journals. Over the last decade, Aline has been participating and coordinating a wide range of research, institutional and business development projects - mostly in the field of financial economics, corporate and regional economic management.

While she started her academic career in the Netherlands, she has been teaching corporate finance, empirical finance and applied econometric courses since mainly at the master and doctoral level at numerous European Universities and has been regularly lecturing at various universities in the Middle East, Africa and Australasia.

She is member of the European Network for Research Evaluation in Social Sciences and Humanities as well as member of many renowned academic financial economics associations. Georges Muller joined cegecom s. In , he became Director of artelis s. He advises clients in a variety of matters such as disputed redundancies, immigration, work permits, pension rights and all types of labour issues, including transfer of employment and social plans.

Marc Neuen, 46 ans, a toujours eu la fibre entrepreneuriale. Il revient au pays chez Commerzbank International et en devient managing director en Voir fiche page Anne-Marie Nicolas, attorney-at-law, is a partner in the Banking and Finance practice group.

She specialises in banking and finance law and acts for banks, financial institutions, corporates and investors in various types of cross-border finance transactions, including acquisition financing, asset financings, structured finance and debt re structuring. She also advises on regulatory, insolvency and corporate governance matters. AnneMarie is admitted to the Luxembourg bar and to the New-York bar and is a member of the banking committee of the Institut Luxembourgeois des Administrateurs.

Keith advises global groups on the design and implementation of tax strategies, with emphasis on pan-European PERE funds. Keith heads global real estate tax at Taxand, the global network of independent tax firms of which ATOZ is a founding member. Keith is instrumental in shaping legislative change in coordination with industry groups.

Als er diese Botschaft erkannte, realisiert er ,was er in seinem Leben machen wollte. Damals konnte Jeff Oberweis seine Worte nicht verstehen. Professor Dr. He is founding director of SnT since He has received the European Research Council advanced research grant twice. In , he began building websites with Gyorgy Gattyan. Karoly and Gyorgy then decided to bring on three more partners to launch livejasmin. Not long after, they expanded their portfolio with the creation of Docler Holding, which Karoly left in to work on several smaller projects.

In , he began developing an online travel platform, Elvoline, and integrated it into the group in Chan regularly represents large groups of companies in the US, Europe, Asia and international and local banks. He received his law degree from the University of Louvain and holds an LL.

His primarily practice focuses on mergers and acquisitions, cross-border corporate restructurings and general counseling on corporate and securities law matters. Guy represents both private equity and corporate clients in domestic and cross-border transactions. He has extensive deal experience across many industry sectors, including significant depth in joint-venture structures and energy related transactions.

He has been an assistant professor at the University of Leuven and Hasselt University. He is in charge of several leading panEuropean fund promoters based in Luxembourg. He has over 18 years of international experience in the alternative fund services sector, including senior postings in Canada, the UK, the Cayman Islands and Guernsey. Throughout his extensive experience serving on operating company and fund boards, he has gained a unique knowhow in serving his clients and anticipating their needs.

He structures private equity real estate and infrastructures funds and also assists family offices. He advises on fund structuring. He is currently a member of the Region Team Latin America and visits the region on a frequent basis.

Marc Payal a rejoint Fujitsu en He is an experienced professional with a successful career in banking, business development, and administration. He speaks fluent Russian and English. He moved to Luxembourg in to support the development of our cross-border activities. Catherine advises fund managers and investors on the structuring and formation of and investment into alternative investment funds, particularly within the private equity, real estate and debt funds sectors.

Catherine is also a regular lecturer on fund formation and structuring for Kluwer and the House of Training. R services with 8 years in Paris and 17 years in Luxembourg for Adecco Group. His involvement in this sector drove him to become also President of the administration council of Fedil Employment Services from www.

HABBO CASINO BETTING AREA

The versatile functions of CKRs in leukocyte biology require a precise regulation of signal initiation and subsequent desensitization after ligand engagement. The modulation of the cell surface density is a key mechanism regulating the signaling activity of all CKRs Neel et al. The fact that all of these diverse CKRs were targeted with comparable efficacy by the identical motifs in Nef from HIV-1 SF2 suggests that a universal, possibly indirect mechanism may be used by the viral protein.

Interestingly, Nef uses the identical motifs to reduce the surface expression of structurally unrelated MHC-I molecules. One model of the Nef-induced receptor modulation postulates that the viral protein acts via a direct physical interaction with the respective receptor Peterlin and Trono, In line with the scarcity of reported interactions, we did not find evidence for a physical association of Nef and CCR5 in coimmunoprecipitation studies from CHO cells data not shown.

In light of the rapidly growing list of only distantly related receptor molecules, the surface exposure of which is modulated by Nef, a more general mode of action, that may not necessarily require physical interaction, seems likely. Recently, a generalized alteration of endocytic vesicle trafficking induced by Nef was proposed as a mechanism for affecting cell surface receptors, including the transferrin receptor Madrid et al.

In line with such distinct sites of Nef action, we found markedly different degrees of concentration dependence for down-regulation of CD4 and CKRs Figure 1 and Supplemental Figure 1. Also relevant in this context, we have recently compared the expression of HIV-1 Nef after transfection of the identical Nef expression plasmids, that were used in the current study, and HIV-1 infection and found comparable expression levels of the viral protein Keppler et al.

Our kinetic endocytosis assays and localization studies revealed that Nef only moderately accelerated the rate of CKR endocytosis. GFP expression plasmids data not shown , it seems likely that mechanisms other than accelerated endocytosis of surface-exposed receptors contribute to this Nef-mediated phenotype.

Conceivably, the sum of such interferences may result in the net reduction of cell surface CKR levels and the pronounced perinuclear accumulation observed at steady state in Nef-expressing cells. Irrespective of the sorting mechanism used, our previous results obtained for CCR5 Michel et al. It is conceivable that Nef acts at the early endosomal compartment Madrid et al. Nef possibly perturbs the rapid recycling of CKRs to the cell surface and reroutes the receptors to a perinuclear compartment.

This compartment may be related to the slow recycling compartment that was found to be involved in normal trafficking of some CKRs Neel et al. In our opinion the resolution of confocal microscopy does not allow a clear distinction between these and other closely adjacent perinuclear compartments.

Our data show that lentiviral Nef proteins have evolved a general strategy to affect the cell surface levels of CKRs. The existence of a mechanism that targets such a broad class of cell surface receptors may reflect the need of HIV to down-modulate both of the divergent major entry coreceptors CCR5 and CXCR4 to efficiently protect productively infected cells from superinfection Michel et al.

However, the newly found Nef activity of down-regulation of at least eight different CKRs is not restricted to those receptors that function as HIV coreceptors. The reduced CKR expression on these cells may disturb the coordinated action of host immune responses against virus-infected cells Esche et al.

At present, there is only limited knowledge about the regulation of the internalization rate and intracellular trafficking of individual CKRs under physiological conditions in the absence or presence of ligand.

In general, parameters known to influence receptor endocytosis include the type and concentration of ligand, composition of the CKR cytoplasmic tail, receptor phosphorylation status, and abundance of endocytosis-associated adaptor molecules in the cytoplasm Neel et al. The mechanism by which lentiviral Nef proteins reduce CKR cell surface exposure differs by several criteria from known pathways used by individual CKRs for internalization and intracellular trafficking.

This contrasts the situation under physiological conditions, during which chemokine ligands are the main trigger for CKR cell surface level reduction that is primarily mediated by an accelerated clathrin-mediated receptor endocytosis.

However, this alternative pathway seems to be restricted to certain cell types and the evaluation of its importance in vivo has so far not been possible Signoret et al. Second, classical endocytosis motifs in the CKR cytoplasmic tail are not required for the Nef-mediated receptor down-modulation. On the contrary, a hallmark of the major clathrin-dependent CKR endocytosis pathway under physiological conditions is its dependence on motifs within the cytoplasmic tail of CKRs that mediate interaction with the adaptor molecule AP Although clathrin-mediated endocytosis may still be involved, our data clearly demonstrate an autonomous regulation of CKR trafficking by Nef that does not require regulatory elements within the cytoplasmic tail.

Neither pharmacological interference nor genetic mutation of critical receptor elements for G protein binding and downstream signaling had an influence on the Nef-mediated CKR down-regulation. One might speculate that the NAA triple-mutation of the CXCR4 DRY box channels the receptor to intracellular sorting pathways that are affected by Nef in a fundamentally different manner thereby resulting in an enhanced cell surface presentation as opposed to the down-regulation of wild-type receptor.

Conceivably, other DRY motif—containing GPCRs may also be a target for Nef-mediated down-regulation from the cell surface and this would be an interesting extension of our present work. Future studies will need to explore their potential role in the modulation of CKR cell surface expression by Nef. Finally, Nef is the first broad-spectrum modulator of CC- and CXC-CKRs cell surface levels, because it affects the cell surface expression of at least eight rather diverse CKRs with comparable efficiencies and diverts these receptors from their individual intracellular trafficking pathway to a probably common perinuclear compartment.

This is in contrast to the individual cell surface turnover rates and the multifaceted internalization and intracellular trafficking pathways of different CKRs under physiological conditions Neel et al. E on June 14, We thank Dr. We thank Drs.

This work was supported by grants from the Deutsche Forschungsgemeinschaft to O. David Gladstone Institutes to O. Molecular Biology of the Cell Vol. This is the final version - click for previous version. Oliver T. Add to favorites Download Citations Track Citations.

View article. Abstract Chemokine receptors CKRs are important physiological mediators of immune defense, inflammatory responses, and angiogenesis, and they have also been implicated in a number of viral disease processes. Nef induces CD4 endocytosis: requirement for a critical dileucine motif in the membrane-proximal CD4 cytoplasmic domain. Cell 76 , Nef: agent of cell subversion. Microbes Infect. Chemokine receptors as HIV-1 coreceptors: roles in viral entry, tropism, and disease.

Cell , Promiscuous use of CC and CXC chemokine receptors in cell-to-cell fusion mediated by a human immunodeficiency virus type 2 envelope protein. Virology , Detection of human immunodeficiency virus type 1 Nef and CD4 physical interaction in living human cells by using bioluminescence resonance energy transfer. Identification of CXCR4 domains that support coreceptor and chemokine receptor functions.

USA , Pseudotype formation of murine leukemia virus with the G protein of vesicular stomatitis virus. Chemokines: key players in innate and adaptive immunity. Live and let die: Nef functions beyond HIV replication. Immunity 16 , Serine phosphorylation-independent downregulation of cell-surface CD4 by nef.

Nature , Structure—function relationships in HIV-1 Nef. EMBO Rep. EMBO J. The HIV-1 pathogenicity factor nef interferes with maturation of stimulatory T-lymphocyte contacts by modulation of N-wasp activity. Nef proteins from diverse groups of primate lentiviruses downmodulate CXCR4 to inhibit migration to the chemokine stromal derived factor 1. Chemokine inhibition—why, when, where, which and how? Google Scholar Kasper M. Rodent cells support key functions of the human immunodeficiency virus type 1 pathogenicity factor Nef.

Susceptibility of rat-derived cells to replication by human immunodeficiency virus type 1. Characterization of sequence determinants within the carboxyl-terminal domain of chemokine receptor CCR5 that regulate signaling and receptor internalization. Human immunodeficiency virus type 1 Nef activates pactivated kinase via recruitment into lipid rafts. The role of receptor kinases and arrestins in G protein-coupled receptor regulation. Mutation of the DRY motif reveals different structural requirements for the CC chemokine receptor 5-mediated signaling and receptor endocytosis.

Human immunodeficiency virus type 1 Nef mediates sustained membrane expression of tumor necrosis factor and the related cytokine LIGHT on activated T cells. The chemokine monocyte chemotactic protein 1 triggers Janus kinase 2 activation and tyrosine phosphorylation of the CCR2B receptor. The Nef protein of human immunodeficiency virus establishes superinfection immunity by a dual strategy to downregulate cell-surface CCR5 and CD4.

Pathways for internalization and recycling of the chemokine receptor CCR5. Blood 99 , International union of pharmacology. Nomenclature for chemokine receptors. Chemokine receptor internalization and intracellular trafficking. Cytokine Growth Factor Rev. Hide, shield and strike back: how HIV-infected cells avoid immune eradication.

Biological analysis of human immunodeficiency virus type 1 R5 envelopes amplified from brain and lymph node tissues of AIDS patients with neuropathology reveals two distinct tropism phenotypes and identifies envelopes in the brain that confer an enhanced tropism and fusigenicity for macrophages.

Cell Biol. Effects of CCR5 and CD4 cell surface concentrations on infections by macrophagetropic isolates of human immunodeficiency virus type 1. Mutation of a highly conserved aspartic acid in the beta2 adrenergic receptor: constitutive activation, structural instability, and conformational rearrangement of transmembrane segment 6. Blood , The biology of chemokines and their receptors. The activation process of the alpha1B-adrenergic receptor: potential role of protonation and hydrophobicity of a highly conserved aspartate.

USA 94 , Down-modulation of mature major histocompatibility complex class II and up-regulation of invariant chain cell surface expression are well-conserved functions of human and simian immunodeficiency virus nef alleles. Endocytosis of major histocompatibility complex class I molecules is induced by the HIV-1 Nef protein. The human formyl peptide receptor as model system for constitutively active G-protein-coupled receptors.

Life Sci. Agonist-induced endocytosis of CC chemokine receptor 5 is clathrin dependent. Cell 16 , Cell Sci. Viral hijacking of G-protein-coupled-receptor signalling networks. Human immunodeficiency virus Nef induces rapid internalization of the T-cell coreceptor CD8alphabeta. Toggle navigation RocketReach.

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Carissa Cinda lordtime. Picked up 3 salads with chicken. Dick and Angel give Jonny their tips and tricks on how to find the perfect Chateau, without falling into a money pit. Jonathan and Michael try to start making money through booking a wedding of an American couple. Also, Dick and Angel help Jonnie and Ashley search for their own chateau.

Philip and Angelina get a visit from Dick, and with his engineering expertise; helps them build a bridge for the chateau. Meanwhile, Jonny and Ashley are still hunting for their dream Chateau. Jonathan and Michael hunt for treasure in their caves of the Chateau; treasure in the form of a stash of wine from World War II. On the other hand, Fiona starts renovations in the dining room. Jonathan and Michael have help from investors to keep their dreams of renovating the chateau afloat, however their meeting with the investors about keeping their goats did not go well.

Philip and Angelina must fix the toilet at their own anniversary party. Mandy and Steve have decided to build a swimming pool at their chateau in the Dordogne. With that comes preparation, and several problems; notably a sewage issue that threatens the whole first floor. Steve and Mandy are stilling having pool problems.

The first wedding guests of the series are here. With that, Angel shows Michael and Jonathan tips to keep wedding costs low but enhance the experience. For Mandy and Steve, the pool continues to be an issue. New couple, Tim and Kys join the show in the Dordogne. Colette and Paul try to launch a new menu. Donna believes a horde of ancient armour was hidden in her chateau's lake. Dick and Donna's search for the armour in the lake continues. Tim and Krys struggle getting the attic converted in time.

Dick's building a compost toilet for use at outside weddings, Billy and Gwendoline want to open their chateau as a wedding location, and Clive and Tanith need to win over the locals. Billy needs to repoint the chimney, however, the task is a lot more difficult than it sounds due to the fact that he is afraid of heights.

Meanwhile, time is running out for Marian and Tanya, plus Clive and Tanith get stuck into some hard labour. Billy, Gwendoline and Michael want to finally move into their chateau, however, the kitchen is still not finished. Paul and Karen from Chateau La Perriere devise a plan to get more bookings. Clive and Tanith try to bring a couple together. Billy and Gwendoline have a boar that's making a mess off the property, which needs hunting.

Clive and Tanith utilise their garden by making a dish out of its content. Paul from Chateau La Perriere attempts to convert the water tower into an office. Billy and his dad do some DIY with levelling the patio. Paul and Karen from Chateau La Perriere finish their office conversion. Meanwhile, Clive inspects a strange nest in his orangery. Tim and Margreeth plan to sell ' gite timeshares ', which is a form of holiday renting to increase income and returning customers.

Nicole and Stephan choose to convert their hall into a tearoom. Alison and Paul are adding to the chateau features by creating a 'wedding terrace'. Nicole asks Angel for some styling advice about wallpaper. Easter is coming and Tim and Margreeth are getting prepared. Meanwhile, Paul and Alison show off their new wedding terrace with a party.

Tim and Margreeth concentration is on refurbishing a caravan in their park. Sophie and James need to get some funds fast if they are to keep their chateau afloat. Tim and Margreeth get started on their new business venture with research. Stephanie's singles weekend event is here.

Sophie and James hold a walking event near their chateau. Dick Strawbridge joins Elaine and David as they search for the dream chateau, and Tim and Krys are revisited as they prepare to re-launch their business. Couple Tim and Krys race to get their chateau ready for their guests; Elaine and David visit a 17th-century ex-priory in Normandy; and Steve and Angela refurbish a master bedroom.

Belinda travels to Dick and Angel's chateau to learn the art of decoupage, and wannabe chateau owners Elaine and David visit a 19th-century chateau with 18 rooms and two gites. Dick shows Tim how to put on a gourmet weekend, and Angel has a heart-to-heart chat about chateau-living with Krys.

For Belinda and Lee, it's arrival day for their first guests. Tim and Krys have their first gastronomic weekend; Belinda and Lee host their biggest event so far with dancing and a slap-up meal; and Dick visits Angela and Steve to lend a hand. Dick helps Tim and Rebecca find their feet in a dilapidated chateau with no plumbing. Edward and Anna expect guests in their fairy-tale chateau, but things don't go to plan. Tim and Rebecca call in their mates to help with restoration work.

Dick and Angel host a very special wedding for close friends. Motorcycle-mad couple Martin and Kim search for the perfect chateau. Tim and Rebecca battle to get their chateau looking tip top for a tour operator. Tim and Rebecca receive a booking and prepare for their first paying guests.

Martin and Kim take their chateau search up a gear. Paul and Karen from Chateau La Perriere set out to create a cinema room. Anna and Edward host another big wedding, but Edward's out of action. Dick visits Tim and Rebecca as they run into problems. Karen from Chateau La Perriere does all she can to bag her and Paul's first wedding.

Chateau maintenance tasks include looking after an elevated pool and a maze, and preparing for the fast approaching wedding season. Dick helps Paul cut some Vitrolite vintage tiles for an art deco bathroom, Abbie gets on with painting bedroom furniture, and Julia and her sisters visit two more chateaux. Couple Mariam and Johnno arrive at their new chateau with teenage son Monty, to discover that they have no running water and builders are busy in every room.

Emma and Paul urgently need to fill their lake ready for the artists' retreat they're hosting. Abbie and Karen get tips from Angel on how to save money for their wedding business. Emma and Paul invite locals - including the mayor - to view the work they've done on the front of their chateau.

But first Paul has to design, build and fit two heavy balconies. More adventurous chateau owners live their castle dreams. Dick steps in to help new chateau owners couple Erin and JB. Tim and Margareeth embark on their next money-making venture.

Dick fixes up his temperamental van at his chateau. Alison and Paul make an exciting discovery. Erin and JB host a 90th birthday party. May and her family start work turning a rundown outbuilding into a yoga retreat. For Tim and Margareeth, It's the day of the wedding party. Dick steps in to help Erin and JB find a solution to their rusted hinges.

Wedding season is over for Tim and Margareeth. May and her son Jack get the Yoga Room ready. Erin and JB are launching their chateau business by opening it up for a tea party. British artist Johnny and his girlfriend Ashley plan to host artist workshops. Musicians Ben and Billie want to put on foodie events. Nicole and Stefan return with a new venture. Nicole and Stefan start work on the ancient gatehouse. Billie visits Angel to pick up some ideas for natural designs. Johnny and Ashley talk to Dick about work on their library.

Dick helps restore Ben's traditional wine press. Johnny and Ashley finish the library ceiling with a nude painting of Ashley. Stefan has a last-minute dash to finish an apartment. It's National Monuments Day at Nicole and Stefan's castle and the gatehouse refurbishment is put on hold. Wendy and Marcus launch their wedding business with a raucous hen party.