A human T-cell leukemia virus type 1 regulatory element enhances the immunogenicity of human immunodeficiency virus type 1 DNA vaccines in mice and nonhuman primates.
Plasmid DNA vaccines elicit potent and protective immune responses in numerous small-animal models of infectious diseases. However, their immunogenicity in primates appears less potent. Here we investigate a novel approach that optimizes regulatory elements in the plasmid backbone to improve the immunogenicity of DNA vaccines. Among various regions analyzed, we found that the addition of a regulatory sequence from the R region of the long terminal repeat from human T-cell leukemia virus type 1 (HTLV-1) to the cytomegalovirus (CMV) enhancer/promoter increased transgene expression 5- to 10-fold and improved cellular immune responses to human immunodeficiency virus type 1 (HIV-1) antigens. In cynomolgus monkeys, DNA vaccines containing the CMV enhancer/promoter with the HTLV-1 R region (CMV/R) induced markedly higher cellular immune responses to HIV-1 Env from clades A, B, and C and to HIV-1 Gag-Pol-Nef compared with the parental DNA vaccines. These data demonstrate that optimization of specific regulatory elements can substantially improve the immunogenicity of DNA vaccines encoding multiple antigens in small animals and in nonhuman primates. This strategy could therefore be explored as a potential method to enhance DNA vaccine immunogenicity in humans.
Barouch
Dan H
DH
Division of Viral Pathogenesis, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts 02215, USA.
Yang
Zhi-yong
ZY
Kong
Wing-pui
WP
Korioth-Schmitz
Birgit
B
Sumida
Shawn M
SM
Truitt
Diana M
DM
Kishko
Michael G
MG
Arthur
Janelle C
JC
Miura
Ayako
A
Mascola
John R
JR
Letvin
Norman L
NL
Nabel
Gary J
GJ
D016475:3T3 Cells; D016915:AIDS Vaccines / Q000276:immunology*; D000818:Animals; D005809:Genes, Regulator / Q000502:physiology*; D015497:HIV-1 / Q000276:immunology*; D015368:Human T-lymphotropic virus 1 / Q000235:genetics*; D007114:Immunization; D007371:Interferon-gamma / Q000096:biosynthesis; D008252:Macaca fascicularis; D051379:Mice; D008807:Mice, Inbred BALB C; D010957:Plasmids; D020079:Terminal Repeat Sequences; D019444:Vaccines, DNA / Q000276:immunology*; D014779:Virus Replication
D016915:AIDS Vaccines; D019444:Vaccines, DNA; D007371:Interferon-gamma