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Bianchi, Alessia (2009) Construction and characterization of infectious inter-genotypic Hepatitis C Virus chimeras. [Tesi di dottorato]

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Abstract (inglese)

A major impediment in Hepatitis C Virus (HCV) research and drug development has been the lack of a culture system supporting virus production. This obstacle was recently overcome by using JFH1-based full-length genomes that allow the production of infectious viruses both in vitro and in vivo. Despite such improvement, the system was restricted to two structural gene sequences (JFH1 and J6), both derived from the genotype 2a, limiting comparative studies between different HCV strains. The system was thus extended by the creation of a series of inter-genotypic HCV chimeras that allow the production of infectious genotypes 1a, 1b and 3a particles, even if with a less efficiency in terms of productivity compared with the wild type JFH1 strain.
In the present study, based on the JFH1 strain, we generated two novel chimeric HCV constructs in which only the sequences encoding for the E1 and/or E2 glycoprotein ectodomains are substituted from JFH1 to the Con1 strain (genotype 1b). The entire structural region is maintained of the infectious strain JFH1, with the exception of the soluble portion of E1 and/or E2, allowing comparative analysis of the impact of such regions on virus morphogenesis.
Both JFH1/Con1E1E2 and JFH/Con1E2 chimeric constructs are able to replicate in hepatic cells. Importantly, we demonstrate for the first time that the E1E2 heterodimer formation is not hampered by the ectodomain swapping since glycoproteins from genotypes 2a and 1b can correctly interact each other. Nevertheless, none of the chimeric constructs allow the production of infectious viral particles. This evidence first suggests a specific role of E1 and E2 glycoproteins in HCV particle morphogenesis, and it is corroborated by several experiments. In particular we examined the JFH/Con1E2 construct, in which only the E2 ectodomain region is swapped from genotype 2a to 1b, by confocal microscopy analysis, trans-complementation experiments and by evaluating the presence of HCV infectious particle precursor within transfected cells. Overall our data provide strong evidences that the E2 ectodomain is involved in the HCV assembly through a genotype-specific interplay with the remaining viral structural proteins. As consequence, in the case of inter-genotypic chimeras, genetic incompatibility between JFH1 backbone and the E2 structural protein of genotype 1b dramatically affects the production of viral particles in our system. One of the most likely involved protein in such interactions seems to be NS2, the role of which was recently demonstrated as crucial in the HCV assembly/release processes. However this remains a hypothesis that needs to be verified in order to define the relationships among HCV proteins.

Abstract (italiano)

Il maggior ostacolo allo sviluppo di terapie anti HCV è rappresentato dalla mancanza di culture cellulari che supportano efficacemente la produzione di virus. Questo ostacolo è stato recentemente superato grazie all’isolamento di un clone, denominato JFH1 (genotipo 2a), il cui genoma porta alla produzione di particelle virali infettive sia in vitro che in vivo. Anche se tale sistema cellulare (HCVcc) rappresenta un’importante conquista, presenta il grosso limite della dipendenza dal subtipo JFH1 e da una chimera intra-genotipica in cui la regione strutturale deriva dal subtipo J6, comunque di genotipo 2a. Per effettuare studi comparativi su diversi genotipi, sono stati quindi ingegnerizzati virus chimerici inter-genotipici in cui la prima metà del genoma di JFH1 (dal 5’- UTR alla proteina NS2) è stata sostituita con l’analoga regione proveniente da altri genotipi.
Nel presente lavoro sono state costruite due chimere inter-genotipiche con una nuova strategia. A differenza delle precedenti, la regione strutturale è stata mantenuta interamente di JFH1, ad eccezione della porzione solubile (ectodominio) di una o entrambe le proteine dell’envelope E1 e E2. In questo modo è stato possibile analizzare il ruolo di tale regione, ed in particolare dell’ectodominio di E2, nella produzione di particelle infettive di HCV.
I risultati riportati dimostrano per la prima volta che proteine dell’envelope derivanti da genotipi diversi (nello specifico E1 di genotipo 2a ed E2 di genotipo 1b) possono correttamente interagire a formare dimeri E1E2, rappresentanti la forma funzionale delle proteine dell’envelope. Ciononostante nessuno dei due costrutti chimerici prodotti ha portato all’ottenimento di particelle virali infettive, indicando la presenza di determinanti all’interno della porzione sostituita importanti per la produzione di HCV. In particolare, grazie ad esperimenti di microscopia confocale, analisi della presenza di precursori virali all’interno delle cellule trasfettate ed esperimenti di trans-complementazione, per la prima volta dimostriamo che la regione ectodominica della proteina dell’envelope E2 è fortemente implicata nell’assemblaggio di nuovi virioni, probabilmente attraverso interazioni genotipo-specifiche con altre proteine strutturali. Di conseguenza, nel nostro sistema, la produzione di particelle virali risulta drasticamente alterata a causa dell’incompatibilità genetica tra il backbone JFH1 e la porzione ectodominica di E2 derivante da genotipo 1b. Dato che recentemente è stato riportato un ruolo chiave per NS2 nel processo di assemblaggio, la nostra ipotesi è che una delle interazioni genotipo-specifiche richieste coinvolga per l’appunto E2 nella sua regione solubile e la proteina non strutturale NS2. Quest’ipotesi rimane comunque da approfondire con ulteriori esperimenti atti a meglio definire il tipo di relazione tra proteine virali e il ruolo di tali interazioni nell’assemblaggio di nuovi virioni.

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Tipo di EPrint:Tesi di dottorato
Relatore:Montecucco , Cesare
Correlatore:Merola, Marcello
Dottorato (corsi e scuole):Ciclo 21 > Scuole per il 21simo ciclo > BIOSCIENZE > BIOLOGIA CELLULARE
Data di deposito della tesi:27 Gennaio 2009
Anno di Pubblicazione:03 Gennaio 2009
Parole chiave (italiano / inglese):HCV, chimeric virus, envelope proteins
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/11 Biologia molecolare
Struttura di riferimento:Dipartimenti > Dipartimento di Scienze Biomediche Sperimentali
Codice ID:1461
Depositato il:27 Gen 2009
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