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Fallarino, Lorena (2018) Anti HIV-1 gene therapy approach combining multiple siRNAs with the membrane-anchored fusion inhibitor C-peptide maC46. [Ph.D. thesis]

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Abstract (english)

The development of highly active anti-retroviral therapy (HAART) has considerably improved life expectancy of HIV-1 positive patients by transforming this infection, which once was lethal, into a manageable chronic illness. Although a significant suppression of viral replication under undetectable level is guaranteed following a constant therapeutic adherence, this therapy fails to completely eliminate the infection due to the persistence of HIV-1 into reservoirs, which represent therefore the main obstacle to a definite cure. Furthermore, a lifelong adherence to treatment is associated with drug toxicities and persistent immune dysfunction, which can lead to discontinuation of therapy and the onset of drug resistance. These hurdles, together with the high economic costs of providing HAART to more than 35 million people, which are currently affected by HIV-1, contribute to render HIV-1/AIDS pandemic one of the most important global health challenge. In this scenario, the search for a curative strategy is necessary. Recent successes in inherited immune deficiencies treatment and cancer immunotherapy have raised interest in gene and cell modification to treat HIV-1 infection with the final aim of inducing permanent resistance to HIV-1. In particular, anti HIV-1 gene therapy (GT) protocols, based on engineering of autologous T cells or their progenitors, such as the CD34+ hematopoietic stem cells (HSCs), appear a promising approach to repopulate the immune system after a single therapeutic intervention. Long-term HIV-1 remission in the “patient of Berlin”, who received an heterologous stem cell transplant for acquired immunodeficiency syndrome-related lymphoma from a CCR5 homozygous null HLA-matched donor (CCR5 -/-), even after discontinuation of conventional therapy, has energized the field. However, due to the limited chance of finding matching Δ32 CCR5 donors, recapitulating this clinical success on a large scale appears to be difficult. Moreover, autologous regimens are potentially less toxic, as they may not require full bone marrow ablation or subsequent immune suppression for engraftment. In this setting, the goal would be to disable the CCR5 gene in enough target cells to confer benefit and transplanted back into the patient. Different GT strategies to artificially disrupt the CCR5 gene or transcript have proved to be successful in primary T cells, HSCs, as well as in humanized mice, and are recently been tested in clinical trials. Inhibitors of entry or of early step of viral replication prior the virus integration are expected to lead an advantage selection of gene modified cells, thus preventing the establishment of chronic HIV-1 infection and limit the continued replenishment of viral reservoirs. However, a major goal of gene therapy is to target simultaneously multiple viral sites and endogenous host factors, interfering with different steps of viral cycle, hoping to reduce the onset of virus variants. Among antiviral agents, small interfering RNAs (siRNAs) are less immunogenic than protein-based ones and represent a powerful tool to silence gene expression post-transcriptionally in a sequence specific manner. In order to obtain a stable and long expression, necessary for a chronic disease, multiple anti-HIV-1 siRNAs can be accommodated into self-inactivating (SIN) lentiviral vectors, which are currently preferred for their ability to efficiently transduce target cells, and then because they confer a potentially safer integration site profile, compared to gammaretroviral vectors. For these reasons, different combinatorial platforms based on SIN lentiviral vectors were previously developed to express multiple siRNAs against highly conserved regions of cellular and viral genes, including the cellular co-receptor CCR5, the vif and tat/rev viral factors, involved in different phases of HIV-1 replication and pathogenesis. These siRNAs were placed under the control of different human Polymerase III promoters (such as U6, 7SK and H1) either as independent transcriptional units or as extended short hairpin RNA (e-shRNA), able to express the three siRNA under the control of a single promoter. The most potent antiviral activity in transduced human primary CD4+ T lymphocytes was conferred by two effective anti-HIV-1 combinatorial vectors (i.e. pLL3.7 U6shCCR5-7SKshvif-H1lhtat/rev and pLL3.7 H1e-shRNA). However, HIV-1 can use an alternative coreceptor (i.e. CXCR4) for entering into target cells, that is less favored as target of siRNA or novel gene-editing technologies, because its disruption can compromise fundamental physiological functions, especially the maturation of HSCs. At the same time, CXCR4 tropic viruses are relevant in the pathogenesis of AIDS. Thus, to improve the efficacy of this approach, the two selected vectors were optimized by the insertion of a small membrane anchored C-peptide (maC46) fusion inhibitor, which has been shown to protect against a broad range of HIV-1 isolates and it has been tested in a phase 1 clinical trial. When expressed on target cell surface, the maC46 peptide, which derives from the C-terminal heptad repeat (HR2) of the HIV-1 gp41 envelope glycoprotein, blocks the membrane fusion by interacting with the N-terminal coiled coil domain of the gp41 intermediate structure and preventing the six-helix bundle formation. In these constructs, the expression of the peptide, either fused in frame with the enhanced green fluorescence protein (eGFP) or alone, is driven by the human Elongation Factor 1 promoter (EF1), a cellular-derived enhancer/promoter, which has been shown to confer high level of transgene expression in HSCs and a more safety profile, since decreased cross-activation of nearby promoters. Additionally, the new developed lentiviral vectors carries an optimized version of the Woodchuck hepatitis virus post-transcriptional regulatory element (WPRE*), which enhances the vector titer and lacks oncogenic properties. Furthermore, control vectors either lacking the maC46 encoding sequence or characterized by a scrambled sequence in place of the siRNA encoding ones were generated. Once transfected into different cell lines, the developed vectors led to the expression of the maC46 peptide, that correctly localized at the plasma membrane, as shown with immunofluorescence cell staining. Furthermore, recombinant lentiviral particles (RLVPs) were produced and titrated either using Reverse Transcriptase (RT) Assay and Fluorescence-activated cell sorting (FACS). The efficacy of the maC46 peptide fusion inhibitor, in combination with the silencing activity of the expressed siRNAs, was evaluated in challenge experiments, in which transduced T lymphoblastoid Jurkat cells were infected with HIV-1 HXBc2 Vpr+/Vpu+/Nef+ R4-tropic molecular clone at different multeplicity of infection (M.O.I.). In parallel, in collaboration with the Baum’s group at the Department of Experimental Hematology of the Hannover Medical School, the mutagenic potential of these vectors was assessed by means of in vitro immortalization assay. The results obtained so far clearly show that the optimized vectors, combining for the first time a potent fusion inhibitor with three short hairpin (sh)RNAs, appear to be extremely promising as anti-HIV-1 approach. Importantly, these vectors showed a strongly reduced insertional transformation potential compared to a positive gammaretroviral control vector. This strategy could be now extended to primary cells and in particular to HSCs, the ultimate target of this gene therapy approach, with the final aim of accomplishing a high level of protection from HIV-1 infection over sustained lengths of time, without cell toxicity, and loss of stemness, proliferation capability and differentiation potential for possible future clinical applications.

Abstract (italian)

La storia naturale dell’infezione da HIV-1 e il relativo approccio terapeutico hanno stimolato la comunità scientifica a porsi una serie di interrogativi. Negli ultimi anni sono state introdotte diverse classi di nuovi farmaci, tra cui inibitori nucleosidici e nucleotidici della trascrittasi inversa (NRTI), inibitori non nucleosidici della trascrittasi inversa (NNRTI), inibitori della proteasi (PI), dell’integrasi (IN), inibitori di entrata (i.e. antagonisti del corecettore CCR5 e inibitori di fusione), in grado di ridurre notevolmente la carica virale per ristabilire un certo grado di immunocompetenza da parte dell’ospite e sono stati sperimentati protocolli terapeutici caratterizzati da loro combinazioni, come avviene nel regime polifarmacologico della “terapia antiretrovirale altamente attiva” (HAART). Tuttavia, questi trattamenti non sono ancora del tutto esenti da limiti. Infatti, la non eradicabilità dell’infezione, correlata alla persistenza del virus in determinati distretti anatomici e cellulari (reservoir di infezione), obbliga ad un regime terapeutico a tempo indefinito, imponendo, quindi, nuove problematiche quali l’insorgenza di specie virali farmaco-resistenti, la tossicità d’organo, le interazioni farmacologiche dei farmaci somministrati e, non ultimi, gli elevati costi. Ciò ha favorito e incrementato lo sviluppo di strategie alternative e/o complementari per la cura dell’infezione da HIV-1. Il primo importante successo nella cura dell’infezione da HIV-1 è stato ottenuto in un paziente leucemico HIV-1-positivo, in seguito al trapianto allogenico di cellule staminali ematopoietiche (HSCs), intrinsecamente resistenti all’infezione a causa di una delezione a livello del corecettore virale CCR5 (recettore C-C per le chemochine di tipo 5). Tuttavia, il potenziale rischio di rigetto e la difficoltà di reperire donatori compatibili, non ne consentono un’applicazione diffusa. Pertanto, un possibile approccio alternativo è rappresentato dalla terapia genica, finalizzata all’espressione di geni anti-HIV-1 nelle cellule bersaglio dell’infezione, preferenzialmente nelle HSCs, cellule totipotenti in grado di differenziarsi verso tutte le linee emopoietiche coinvolte nella patogenesi dell’infezione, per generare un sistema immunitario permanentemente resistente al virus, a seguito di un singolo trattamento. In particolare, gli inibitori dell’ingresso o delle fasi iniziali della replicazione virale che precedono l'integrazione del genoma virale nel DNA cromosomico della cellula ospite possono prevenire l'instaurarsi di una infezione cronica, portando ad un vantaggio selettivo delle cellule modificate. D’altro canto, un ulteriore vantaggio consiste nella possibilità di prevenire le mutazioni che insorgono nel processo di trascrizione inversa. Un obiettivo importante della terapia genica consiste nell’agire contemporaneamente nei confronti di più siti virali e fattori cellulari endogeni, in modo da interferire con diverse fasi del ciclo replicativo, mimando il consolidato approccio terapeutico polifarmacologico, con l’intento di ridurre al minimo la probabilità di insorgenza di varianti virali resistenti. A tal proposito, la strategia degli RNA interference (RNAi) rappresenta un valido strumento per silenziare l'espressione genica post-trascrizionale. Molteplici short hairpin (sh)RNA diretti verso trascritti virali e cellulari possono essere combinati all’interno di un vettore lentivirale “self inactivating” di terza generazione (SIN). Questi vettori sono in grado di conferire un’espressione stabile e duratura nel tempo dei transgeni, grazie all’integrazione nel DNA cromosomico della cellula ospite, caratteristica importante e necessaria ai fini terapeutici di una patologia cronica come l’infezione da HIV-1. Sulla base di tali presupposti, sono state precedentemente sviluppate in laboratorio diverse combinazioni di vettori lentivirali esprimenti small interfering RNA (siRNA) diretti contro regioni altamente conservate di geni target cellulari (come CCR5) e virali (come vif, tat e rev) allo scopo di interferire con diverse fasi del ciclo replicativo di HIV-1. Nello specifico, due short hairpin (sh)RNA, codificanti un singolo siRNA diretto contro il trascritto del gene cellulare CCR5 (shCCR5) e del gene virale vif (shvif) ed un long hairpin (lh)RNA, codificante due siRNA diretti contro il trascritto comune del primo esone dei geni tat e rev (lhtat/rev), sono stati posti sotto il controllo di diversi promotori umani della polimerasi III (tra i quali U6, 7SK, H1), sia come unità trascrizionali indipendenti, sia come extended short hairpin RNA (e-shRNA), in grado di esprimere i tre siRNA sotto il controllo di un singolo promotore. Dopo aver verificato che l’attività di silenziamento dei diversi siRNA fosse stabile e funzionale, studi di inibizione della replicazione virale condotti sia in linee cellulari che in cellule umane primarie, hanno portato all’identificazione di due vettori (pLL3.7 U6shCCR5-7SKshVif-H1lhTat/Rev e pLL3.7 H1e-shRNA), capaci di conferire un’efficiente protezione nei confronti di ceppi di laboratorio di HIV-1. Tuttavia, l’ingresso di HIV-1 all’interno della cellula ospite può essere mediato anche da un altro corecettore, CXCR4, il quale risulta meno favorevole al silenziamento genico da parte di siRNA o alla distruzione ad opera delle emergenti tecniche di gene editing, essendo coinvolto in importanti funzioni fisiologiche, in particolare nel processo di maturazione delle cellule staminali ematopoietiche. Allo stesso tempo, i virus CXCR4-tropici (X4) sono rilevanti nella patogenesi dell' AIDS. Pertanto, con l’intento di conferire una protezione ad ampio spettro, i vettori precedentemente selezionati sono stati ottimizzati mediante l’inserimento di un inibitore di fusione, appartenente alla classe dei peptidi sintetici C, derivati dalla porzione C-terminale della subunità gp41 della glicoproteina dell’envelope di HIV-1. In particolare, è stato dimostrato che la forma di peptide ancorata alla membrana (maC46), quando viene espressa sulla superficie di cellule geneticamente modificate, è in grado di proteggere queste ultime dall’infezione da parte di un’ampia gamma di isolati clinici e di ceppi di laboratorio di HIV-1, fornendo inoltre un notevole vantaggio selettivo rispetto a cellule non esprimenti il peptide. La cassetta trascrizionale di maC46, inserita all’interno dei vettori selezionati come unità singola o in frame con il gene reporter eGFP, è stata posta sotto il controllo del promotore umano Elongation Factor 1 (EF1), in grado di indurre elevati livelli di espressione del transgene in cellule staminali ematopoietiche. Inoltre, i nuovi vettori sviluppati presentano una versione ottimizzata del Wooodchuck Hepatitis Virus post-trascriptional regulatory element (WPRE*), privato del potenziale oncogeno, per garantire maggiore sicurezza dal punto di vista terapeutico, ma al contempo in grado di mantenere gli stessi livelli di espressione del transgene. Dopo aver testato, mediante tecniche di immunofluorescenza diretta, l’effettiva localizzazione del peptide maC46 a livello della membrana cellulare, sono state prodotte particelle lentivirali ricombinanti in cellule embrionali di rene umano (293T), il cui titolo è stato determinato mediante saggio di attività retrotrascrittasica (RT Assay) ed analisi citofluorimetrica (Fluorescence-activated cell sorting, FACS). La valutazione del contributo antivirale del peptide maC46, in combinazione con l’attività di silenziamento, dovuta alla presenza di siRNA espressi dai vettori lentivirali, è stata effettuata in esperimenti di challenge, in cui linee cellulari T-linfoblastoidi CD4+, opportunamente trasdotte con le particelle ricombinanti, sono state infettate con il clone molecolare di HIV-1 HXBc2 Vpr+/Vpu+/Nef+ X4-tropico, utilizzando diverse molteplicità di infezione. Parallelamente, in collaborazione con il gruppo di ricerca del professor Christopher Baum del Dipartimento di Ematologia Sperimentale della Scuola Medica di Hannover, è stato testato il potenziale rischio di mutagenesi inserzionale dei vettori, valutazione indispensabile prima di poter procedere all’impiego del modello animale, alla manipolazione di cellule staminali e, in futuro, ad una applicazione clinica. Per tali motivi, i vettori sono stati sottoposti al saggio di immortalizzazione cellulare in vitro. I risultati ottenuti fino ad ora hanno chiaramente dimostrato che i vettori sviluppati, in cui è stato combinato per la prima volta un potente inibitore di fusione con tre siRNA, sono estremamente promettenti in termini di attività antivirale nella linea cellulare linfoblastoide impiegata. Inoltre, tali vettori si sono dimostrati incapaci di indurre effetti genotossici. L’obiettivo ultimo del più ampio progetto di ricerca, in cui si inserisce il presente lavoro, consiste nell’accertare l’efficacia e la sicurezza di tali vettori in modelli animali, per giungere infine alla manipolazione genetica di HSCs derivanti da pazienti HIV+ affetti da linfoma, i quali rappresentano la popolazione ideale in un contesto clinico eticamente accettabile, poiché sono spesso sottoposti a trapianto di HSCs.

EPrint type:Ph.D. thesis
Tutor:Parolin, Maria Cristina
Ph.D. course:Ciclo 30 > Corsi 30 > MEDICINA MOLECOLARE
Data di deposito della tesi:04 January 2018
Anno di Pubblicazione:04 January 2018
Key Words:Gene therapy HIV-1
Settori scientifico-disciplinari MIUR:Area 05 - Scienze biologiche > BIO/19 Microbiologia generale
Struttura di riferimento:Dipartimenti > Dipartimento di Medicina Molecolare
Codice ID:10555
Depositato il:25 Oct 2018 16:29
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