Design and preclinical evaluation of a multigene human immunodeficiency virus type 1 subtype C DNA vaccine for clinical trial
Journal of General Virology
Institute of Infectious Disease and Molecular Medicine, Division of Medical Virology, University of Cape Town, Observatory, Cape Town 7925, South Africa; MRC/UCT Liver Research Centre, UCT, Observatory, Cape Town 7925, South Africa; National Health Laboratory Services, Groote Schuur Hospital, Cape Town, South Africa; MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford, United Kingdom
In this study, the design and preclinical development of a multigene human immunodeficiency virus type 1 (HIV-1) subtype C DNA vaccine are described, developed as part of the South African AIDS Vaccine Initiative (SAAVI). Genetic variation remains a major obstacle in the development of an HIV-1 vaccine and recent strategies have focused on constructing vaccines based on the subtypes dominant in the developing world, where the epidemic is most severe. The vaccine, SAAVI DNA-C, contains an equimolar mixture of two plasmids, pTHr.grttnC and pTHr.gp150CT, which express a polyprotein derived from Gag, reverse transcriptase (RT), Tat and Nef, and a truncated Env, respectively. Genes included in the vaccine were obtained from individuals within 3 months of infection and selection was based on closeness to a South African subtype C consensus sequence. All genes were codon-optimized for increased expression in humans. The genes have been modified for safety, stability and immunogenicity. Tat was inactivated through shuffling of gene fragments, whilst maintaining all potential epitopes; the active site of RT was mutated; 124 aa were removed from the cytoplasmic tail of gp160; and Nef and Gag myristylation sites were inactivated. Following vaccination of BALB/c mice, high levels of cytotoxic T lymphocytes were induced against multiple epitopes and the vaccine stimulated strong CD8+ gamma interferon responses. In addition, high titres of antibodies to gp 120 were induced in guinea pigs. This vaccine is the first component of a prime-boost regimen that is scheduled for clinical trials in humans in the USA and South Africa. © 2006 SGM.
DNA vaccine; epitope; Gag protein; gamma interferon; glycoprotein gp 160; Human immunodeficiency virus vaccine; Nef protein; plasmid vector; protein antibody; RNA directed DNA polymerase; transactivator protein; virus envelope protein; animal cell; animal experiment; animal model; antibody titer; article; CD8+ T lymphocyte; codon; consensus sequence; controlled study; cytoplasm; developing country; DNA modification; DNA shuffling; drug design; drug manufacture; drug safety; drug screening; drug stability; enzyme active site; epidemic; female; gene delivery system; gene expression; gene inactivation; gene mutation; genetic selection; genetic variability; guinea pig; health program; Human immunodeficiency virus 1; immunogenicity; immunostimulation; mouse; multigene family; myristylation; nonhuman; plasmid; priority journal; serotype; South Africa; United States; AIDS Vaccines; Animals; Drug Design; Drug Evaluation, Preclinical; Genes, env; Genes, gag; Genes, tat; HIV-1; Humans; Mice; Vaccines, DNA; Animalia; Cavia; Cavia porcellus; Human immunodeficiency virus; Human immunodeficiency virus 1