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Design and preclinical evaluation of a multigene human immunodeficiency virus type 1 subtype C DNA vaccine for clinical trial

Wendy A. Burgers^1,

Joanne H. van Harmelen^1,

Tomá Hanke⁴

¹ Institute of Infectious Disease and Molecular Medicine (IIDMM) and Division of Medical Virology, University of Cape Town (UCT), Observatory, Cape Town 7925, South Africa
² MRC/UCT Liver Research Centre, UCT, Observatory, Cape Town 7925, South Africa
³ National Health Laboratory Services, Groote Schuur Hospital, Cape Town, South Africa
⁴ MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, The John Radcliffe, Oxford, UK

Correspondence
Carolyn Williamson
cwilliam{at}curie.uct.ac.za

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.

These authors contributed equally to this work.

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