Obiettivo 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. Campo scientifico natural sciencesbiological sciencesmicrobiologyvirology Programma(i) FP7-PEOPLE - Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Argomento(i) FP7-PEOPLE-2012-IEF - Marie-Curie Action: "Intra-European fellowships for career development" Invito a presentare proposte FP7-PEOPLE-2012-IEF Vedi altri progetti per questo bando Meccanismo di finanziamento MC-IEF - Intra-European Fellowships (IEF) Coordinatore UNIVERSITAIR MEDISCH CENTRUM UTRECHT Contributo UE € 183 469,80 Indirizzo HEIDELBERGLAAN 100 3584 CX Utrecht Paesi Bassi Mostra sulla mappa Regione West-Nederland Utrecht Utrecht Tipo di attività Higher or Secondary Education Establishments Contatto amministrativo Susan Zwaagstra (Ms.) Contatto amministrativo Bridgette Connell Collegamenti Contatta l’organizzazione Opens in new window Sito web Opens in new window Costo totale Nessun dato