Design and preclinical evaluation of a multigene human immunodeficiency virus type 1 subtype C DNA vaccine for clinical trial.
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 gp120 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.
Burgers
Wendy A
WA
Institute of Infectious Disease and Molecular Medicine (IIDMM) and Division of Medical Virology, University of Cape Town (UCT), Observatory, Cape Town 7925, South Africa.
van Harmelen
Joanne H
JH
Institute of Infectious Disease and Molecular Medicine (IIDMM) and Division of Medical Virology, University of Cape Town (UCT), Observatory, Cape Town 7925, South Africa.
Shephard
Enid
E
MRC/UCT Liver Research Centre, UCT, Observatory, Cape Town 7925, South Africa.|Institute of Infectious Disease and Molecular Medicine (IIDMM) and Division of Medical Virology, University of Cape Town (UCT), Observatory, Cape Town 7925, South Africa.
Adams
Craig
C
Institute of Infectious Disease and Molecular Medicine (IIDMM) and Division of Medical Virology, University of Cape Town (UCT), Observatory, Cape Town 7925, South Africa.
Mgwebi
Thandiswa
T
Institute of Infectious Disease and Molecular Medicine (IIDMM) and Division of Medical Virology, University of Cape Town (UCT), Observatory, Cape Town 7925, South Africa.
Bourn
William
W
Institute of Infectious Disease and Molecular Medicine (IIDMM) and Division of Medical Virology, University of Cape Town (UCT), Observatory, Cape Town 7925, South Africa.
Hanke
Tomáš
T
MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford, UK.
Williamson
Anna-Lise
AL
National Health Laboratory Services, Groote Schuur Hospital, Cape Town, South Africa.|Institute of Infectious Disease and Molecular Medicine (IIDMM) and Division of Medical Virology, University of Cape Town (UCT), Observatory, Cape Town 7925, South Africa.
Williamson
Carolyn
C
Institute of Infectious Disease and Molecular Medicine (IIDMM) and Division of Medical Virology, University of Cape Town (UCT), Observatory, Cape Town 7925, South Africa.
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000818:Animals; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D015752:Genes, env / Q000276:immunology; D015750:Genes, gag / Q000276:immunology; D015756:Genes, tat / Q000276:immunology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D051379:Mice; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology
D016915:AIDS Vaccines; D019444:Vaccines, DNA