title: Inhibition of hepatitis B virus replication by helper dependent adenoviral vectors expressing artificial anti-HBV pri-miRs from a liver-specific promoter.
abstract: Research on applying RNA interference (RNAi) to counter HBV replication has led to identification of potential therapeutic sequences. However, before clinical application liver-specific expression and efficient delivery of these sequences remain an important objective. We recently reported short-term inhibition of HBV replication in vivo by using helper dependent adenoviral vectors (HD Ads) expressing anti-HBV sequences from a constitutively active cytomegalovirus (CMV) promoter. To develop the use of liver-specific transcription regulatory elements we investigated the utility of the murine transthyretin (MTTR) promoter for expression of anti-HBV primary microRNAs (pri-miRs). HD Ads containing MTTR promoter effected superior expression of anti-HBV pri-miRs in mice compared to HD Ads containing the CMV promoter. MTTR-containing HD Ads resulted in HBV replication knockdown of up to 94% in mice. HD Ads expressing trimeric anti-HBV pri-miRs silenced HBV replication for 5 weeks. We previously showed that the product of the codelivered lacZ gene induces an immune response, and the duration of HBV silencing in vivo is likely to be attenuated by this effect. Nevertheless, expression of anti-HBV pri-miRs from MTTR promoter is well suited to countering HBV replication and development of HD Ads through attenuation of their immunostimulatory effects should advance their clinical utility.
authors.affiliation: Antiviral Gene Therapy Research Unit, School of Pathology, Health Sciences Faculty, University of the Witwatersrand, Private Bag 3, Johannesburg 2050, South Africa.
authors.forename: Mohube Betty
authors.initials: MB
authors.lastname: Mowa
authors.affiliation: Antiviral Gene Therapy Research Unit, School of Pathology, Health Sciences Faculty, University of the Witwatersrand, Private Bag 3, Johannesburg 2050, South Africa.
authors.forename: Carol
authors.initials: C
authors.lastname: Crowther
authors.affiliation: Antiviral Gene Therapy Research Unit, School of Pathology, Health Sciences Faculty, University of the Witwatersrand, Private Bag 3, Johannesburg 2050, South Africa.
authors.forename: Abdullah
authors.initials: A
authors.lastname: Ely
authors.affiliation: Antiviral Gene Therapy Research Unit, School of Pathology, Health Sciences Faculty, University of the Witwatersrand, Private Bag 3, Johannesburg 2050, South Africa.
authors.forename: Patrick
authors.initials: P
authors.lastname: Arbuthnot
mesh_terms: D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D003587:Cytomegalovirus / Q000235:genetics; D015967:Gene Expression Regulation, Viral; D020868:Gene Silencing; D017930:Genes, Reporter; D005822:Genetic Vectors / Q000378:metabolism*; D057809:HEK293 Cells; D006378:Helper Viruses / Q000378:metabolism*; D006515:Hepatitis B virus / Q000235:genetics / Q000502:physiology*; D006801:Humans; D008099:Liver / Q000378:metabolism*; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D009928:Organ Specificity / Q000235:genetics; D011228:Prealbumin / Q000235:genetics; D011401:Promoter Regions, Genetic; D012319:RNA Polymerase II / Q000378:metabolism; D011995:Recombination, Genetic / Q000235:genetics; D014779:Virus Replication / Q000235:genetics*
chemical_list: D035683:MicroRNAs; D011228:Prealbumin; D012319:RNA Polymerase II