title: Enhanced expression of HIV and SIV vaccine antigens in the structural gene region of live attenuated rubella viral vectors and their incorporation into virions.
abstract: Despite the urgent need for an HIV vaccine, its development has been hindered by virus variability, weak immunogenicity of conserved epitopes, and limited durability of the immune response. For other viruses, difficulties with immunogenicity were overcome by developing live attenuated vaccine strains. However, there is no reliable method of attenuation for HIV, and an attenuated strain would risk reversion to wild type. We have developed rubella viral vectors, based on the live attenuated vaccine strain RA27/3, which are capable of expressing important HIV and SIV vaccine antigens. The rubella vaccine strain has demonstrated safety, immunogenicity, and long lasting protection in millions of children. Rubella vectors combine the growth and immunogenicity of live rubella vaccine with the antigenicity of HIV or SIV inserts. This is the first report showing that live attenuated rubella vectors can stably express HIV and SIV vaccine antigens at an insertion site located within the structural gene region. Unlike the Not I site described previously, the new site accommodates a broader range of vaccine antigens without interfering with essential viral functions. In addition, antigens expressed at the structural site were controlled by the strong subgenomic promoter, resulting in higher levels and longer duration of antigen expression. The inserts were expressed as part of the structural polyprotein, processed to free antigen, and incorporated into rubella virions. The rubella vaccine strain readily infects rhesus macaques, and these animals will be the model of choice for testing vector growth in vivo and immunogenicity.
authors.affiliation: Lab of Immunoregulation, Division of Viral Products, Office of Vaccines, Center for Biologics, FDA, Bldg 29, Room 523, NIH Campus, Bethesda, MD 20892, United States.
authors.forename: Konstantin
authors.initials: K
authors.lastname: Virnik
authors.forename: Yisheng
authors.initials: Y
authors.lastname: Ni
authors.forename: Ira
authors.initials: I
authors.lastname: Berkower
mesh_terms: D016915:AIDS Vaccines / Q000235:genetics* / Q000276:immunology; D000818:Animals; D002522:Chlorocebus aethiops; D015870:Gene Expression; D015683:Gene Products, gag / Q000235:genetics / Q000276:immunology; D005818:Genetic Engineering; D005822:Genetic Vectors / Q000235:genetics*; D015488:HIV Antigens / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015658:HIV Infections / Q000276:immunology; D006801:Humans; D008253:Macaca mulatta / Q000276:immunology / Q000821:virology; D011401:Promoter Regions, Genetic / Q000235:genetics; D011994:Recombinant Proteins / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D012412:Rubella virus / Q000235:genetics* / Q000254:growth & development; D018449:SAIDS Vaccines / Q000235:genetics* / Q000276:immunology; D012692:Serial Passage; D014613:Vaccines, Attenuated / Q000235:genetics*; D014709:Vero Cells; D015678:Viral Structural Proteins / Q000235:genetics; D014771:Virion / Q000235:genetics* / Q000276:immunology*; D014779:Virus Replication; D054299:env Gene Products, Human Immunodeficiency Virus / Q000235:genetics / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D015683:Gene Products, gag; D015488:HIV Antigens; D011994:Recombinant Proteins; D018449:SAIDS Vaccines; D014613:Vaccines, Attenuated; D015678:Viral Structural Proteins; D054299:env Gene Products, Human Immunodeficiency Virus; C115853:simian immunodeficiency virus gag p55