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
Burgers, W.A., Institute of Infectious Disease and Molecular Medicine, Division of Medical Virology, University of Cape Town, Observatory, Cape Town 7925, South Africa; van Harmelen, J.H., Institute of Infectious Disease and Molecular Medicine, Division of Medical Virology, University of Cape Town, Observatory, Cape Town 7925, South Africa; Shephard, E., 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; Adams, C., Institute of Infectious Disease and Molecular Medicine, Division of Medical Virology, University of Cape Town, Observatory, Cape Town 7925, South Africa; Mgwebi, T., Institute of Infectious Disease and Molecular Medicine, Division of Medical Virology, University of Cape Town, Observatory, Cape Town 7925, South Africa; Bourn, W., Institute of Infectious Disease and Molecular Medicine, Division of Medical Virology, University of Cape Town, Observatory, Cape Town 7925, South Africa; Hanke, T., MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford, United Kingdom; Williamson, A.-L., Institute of Infectious Disease and Molecular Medicine, Division of Medical Virology, University of Cape Town, Observatory, Cape Town 7925, South Africa, National Health Laboratory Services, Groote Schuur Hospital, Cape Town, South Africa; Williamson, C., Institute of Infectious Disease and Molecular Medicine, Division of Medical Virology, University of Cape Town, Observatory, Cape Town 7925, South Africa
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.