DNA vaccines encoding membrane-bound or secreted forms of heat shock protein 70 exhibit improved potency.
Traditional vaccine strategies are inefficient against challenge with complex pathogens including HIV; therefore, novel vaccine technologies are required. DNA vaccines are attractive as they are relatively cheap and easy to manufacture, but a major limitation has been their lack of immunogenicity in humans, which may be overcome with the incorporation of an adjuvant. HSP70 is a recognised damage-associated molecular pattern, which is a potential adjuvant. We investigated the immunogenicity of a DNA vaccine encoding HIV gag and HSP70; the latter was genetically modified to produce cytoplasmic, secreted or membrane-bound HSP70, the expression of which was controlled by an independent promoter. The DNA was administered to C57BL/6 mice to evaluate gag-specific T-cell responses. Our results demonstrated the ability of membrane-bound and secreted HSP70 to significantly enhance gag-specific T-cell responses and increase the breadth of T-cell responses to include subdominant epitopes. Membrane-bound or secreted HSP70 also significantly improved the multifunctionality of HIV-specific T cells and T-cell proliferation, which is important for maintaining T-cell integrity. Most importantly, the inclusion of membrane-bound HSP70, secreted HSP70 or a combination significantly increased protection in mice challenged with EcoHIV, a chimeric virus that replicates in mouse leukocytes in vivo.
Department of Surgery, Virology Laboratory, Basil Hetzel Institute, University of Adelaide, Adelaide, Australia.
Tamsin J
TJ
Garrod
Branka
B
Grubor-Bauk
Tessa
T
Gargett
Yanrui
Y
Li
Darren S
DS
Miller
Wenbo
W
Yu
Lee
L
Major
Christopher J
CJ
Burrell
Steven
S
Wesselingh
Andreas
A
Suhrbier
Eric J
EJ
Gowans
D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D003713:Dendritic Cells / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D018840:HSP70 Heat-Shock Proteins / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D041681:NIH 3T3 Cells; D013601:T-Lymphocytes / Q000276:immunology; D014611:Vaccination; D019444:Vaccines, DNA / Q000276:immunology*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000276:immunology
D016915:AIDS Vaccines; D018840:HSP70 Heat-Shock Proteins; D019444:Vaccines, DNA; D054301:gag Gene Products, Human Immunodeficiency Virus; D007371:Interferon-gamma
Adjuvant; DNA vaccines; HSP70