title: A HIV-Tat/C4-binding protein chimera encoded by a DNA vaccine is highly immunogenic and contains acute EcoHIV infection in mice.
abstract: DNA vaccines are cost-effective to manufacture on a global scale and Tat-based DNA vaccines have yielded protective outcomes in preclinical and clinical models of human immunodeficiency virus (HIV), highlighting the potential of such vaccines. However, Tat-based DNA vaccines have been poorly immunogenic, and despite the administration of multiple doses and/or the addition of adjuvants, these vaccines are not in general use. In this study, we improved Tat immunogenicity by fusing it with the oligomerisation domain of a chimeric C4-binding protein (C4b-p), termed IMX313, resulting in Tat heptamerisation and linked Tat to the leader sequence of tissue plasminogen activator (TPA) to ensure that the bulk of heptamerised Tat is secreted. Mice vaccinated with secreted Tat fused to IMX313 (pVAX-sTat-IMX313) developed higher titres of Tat-specific serum IgG, mucosal sIgA and cell-mediated immune (CMI) responses, and showed superior control of EcoHIV infection, a surrogate murine HIV challenge model, compared with animals vaccinated with other test vaccines. Given the crucial contribution of Tat to HIV-1 pathogenesis and the precedent of Tat-based DNA vaccines in conferring some level of protection in animal models, we believe that the virologic control demonstrated with this novel multimerised Tat vaccine highlights the promise of this vaccine candidate for humans.
authors.affiliation: Virology Laboratory, Basil Hetzel Institute, Discipline of Surgery, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Khamis
authors.initials: K
authors.lastname: Tomusange
authors.affiliation: Virology Laboratory, Basil Hetzel Institute, Discipline of Surgery, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Danushka
authors.initials: D
authors.lastname: Wijesundara
authors.affiliation: Virology Laboratory, Basil Hetzel Institute, Discipline of Surgery, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Gummow
authors.affiliation: Royal Australasian College of Surgeons, Adelaide, South Australia, Australia.
authors.forename: Tamsin
authors.initials: T
authors.lastname: Garrod
authors.affiliation: Virology Laboratory, Basil Hetzel Institute, Discipline of Surgery, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Yanrui
authors.initials: Y
authors.lastname: Li
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne VIC, Australia.|Department of Infectious Diseases, Monash University, Melbourne VIC, Australia.
authors.forename: Lachlan
authors.initials: L
authors.lastname: Gray
authors.affiliation: Centre for Biomedical Research, Burnet Institute, Melbourne VIC, Australia.
authors.forename: Melissa
authors.initials: M
authors.lastname: Churchill
authors.affiliation: Virology Laboratory, Basil Hetzel Institute, Discipline of Surgery, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Branka
authors.initials: B
authors.lastname: Grubor-Bauk
authors.affiliation: Virology Laboratory, Basil Hetzel Institute, Discipline of Surgery, University of Adelaide, Adelaide, South Australia, Australia.
authors.forename: Eric J
authors.initials: EJ
authors.lastname: Gowans
mesh_terms: D000818:Animals; D006801:Humans; D051379:Mice; D051017:Apoptosis Regulatory Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D015483:HIV Antibodies / Q000276:immunology; D015658:HIV Infections / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D015497:HIV-1 / Q000187:drug effects / Q000276:immunology / Q000472:pathogenicity; D007111:Immunity, Cellular; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D000077022:Survivin; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics / Q000276:immunology
chemical_list: D051017:Apoptosis Regulatory Proteins; D015483:HIV Antibodies; C512124:HIV-TAT-survivin (T34A) protein; D011993:Recombinant Fusion Proteins; D000077022:Survivin; D054322:tat Gene Products, Human Immunodeficiency Virus; D019444:Vaccines, DNA