SWITCHR5-X4

Determinants of the switch from R5- to X4-tropic virus in HIV-1 infected individuals

 Coordinatore UNIVERSITAIR MEDISCH CENTRUM UTRECHT 

 Organization address address: HEIDELBERGLAAN 100
city: UTRECHT
postcode: 3584 CX

contact info
Titolo: Ms.
Nome: Susan
Cognome: Zwaagstra
Email: send email
Telefono: +31 887553017

 Nazionalità Coordinatore Netherlands [NL]
 Totale costo 183˙469 €
 EC contributo 183˙469 €
 Programma FP7-PEOPLE
Specific programme "People" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013)
 Code Call FP7-PEOPLE-2012-IEF
 Funding Scheme MC-IEF
 Anno di inizio 2013
 Periodo (anno-mese-giorno) 2013-10-01   -   2016-12-15

 Partecipanti

# participant  country  role  EC contrib. [€] 
1    UNIVERSITAIR MEDISCH CENTRUM UTRECHT

 Organization address address: HEIDELBERGLAAN 100
city: UTRECHT
postcode: 3584 CX

contact info
Titolo: Ms.
Nome: Susan
Cognome: Zwaagstra
Email: send email
Telefono: +31 887553017

NL (UTRECHT) coordinator 183˙469.80

Mappa


 Word cloud

Esplora la "nuvola delle parole (Word Cloud) per avere un'idea di massima del progetto.

coreceptor       relative    cell    levels    switching    cd    switch    affinity    ccr    activation    viral    variants    cxcr    coreceptors    immune    envelope    hiv   

 Obiettivo del progetto (Objective)

'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 and ultimately in our understanding of HIV-1 pathogenesis.'

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