Objectif HIV-1 variants utilizing CCR5 (R5) are predominant during early infection, emergence of CXCR4 (X4) strains typically occurs later. Although R5 to X4 switch is strongly correlated with increased rates of disease progression, it remains largely unknown which factors are causing the switch. Based on our preliminary data we postulate that both host (immune activation) and viral factors (target cell affinity) are required for switching.A) We hypothesize that high levels of immune activation predispose for a coreceptor switch.This will be longitudinally analysed in the Amsterdam Cohort. In parallel, the occurrence of R5-X4 switching will be investigated in African Cohorts with high TB prevalence inducing significant levels of immune activation.B) Our observation that CCR5-inhibitor therapy results in rapid outgrowth of pre-existing X4-variants without affecting the viral setpoint suggests direct competition between R5 and X4-using variants. We will study if increased target cell affinity of the X4 virus facilitates the coreceptor switch. This will be analyzed with the affinofile assay to determine relative envelope affinities for CD4 and CCR5 or CXCR4 between R5 and X4-variants from the same patients and the absence and presence of factors influencing co-receptor switch as identified in part A will also be tested. Finally relative envelope affinity for its different binding partners (CD4 and the coreceptors) will be verified with solubilized coreceptors using surface plasmon resonance.This study will provide important insights into determinants of coreceptor switching andultimately in our understanding of HIV-1 pathogenesis. Champ scientifique natural sciencesbiological sciencesmicrobiologyvirology Programme(s) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Thème(s) FP7-PEOPLE-2012-IEF - Marie-Curie Action: "Intra-European fellowships for career development" Appel à propositions FP7-PEOPLE-2012-IEF Voir d’autres projets de cet appel Régime de financement MC-IEF - Intra-European Fellowships (IEF) Coordinateur UNIVERSITAIR MEDISCH CENTRUM UTRECHT Contribution de l’UE € 183 469,80 Adresse HEIDELBERGLAAN 100 3584 CX Utrecht Pays-Bas Voir sur la carte Région West-Nederland Utrecht Utrecht Type d’activité Higher or Secondary Education Establishments Contact administratif Susan Zwaagstra (Ms.) Contact administratif Bridgette Connell Liens Contacter l’organisation Opens in new window Site web Opens in new window Coût total Aucune donnée
