Augmentation and suppression of immune responses to an HIV-1 DNA vaccine by plasmid cytokine/Ig administration.
The use of cytokines has shown promise as an approach for amplifying vaccine-elicited immune responses, but the application of these immunomodulatory molecules in this setting has not been systematically explored. In this report we investigate the use of protein- and plasmid-based cytokines to augment immune responses elicited by an HIV-1 gp120 plasmid DNA vaccine (pV1J-gp120) in mice. We demonstrate that immune responses elicited by pV1J-gp120 can be either augmented or suppressed by administration of plasmid cytokines. A dicistronic plasmid expressing both gp120 and IL-2 induced a surprisingly weaker gp120-specific immune response than did the monocistronic pV1J-gp120 plasmid. In contrast, systemic delivery of soluble IL-2/Ig fusion protein following pV1J-gp120 vaccination significantly amplified the gp120-specific immune response as measured by Ab, proliferative, and CTL levels. Administration of plasmid IL-2/Ig had different effects on the DNA vaccine-elicited immune response that depended on the temporal relationship between Ag and cytokine delivery. Injection of plasmid IL-2/Ig either before or coincident with pV1J-gp120 suppressed the gp120-specific immune response, whereas injection of plasmid IL-2/Ig after pV1J-gp120 amplified this immune response. To maximize immune responses elicited by a DNA vaccine, therefore, it appears that the immune system should first be primed with a specific Ag and then amplified with cytokines. The data also show that IL-2/Ig is more effective than native IL-2 as a DNA vaccine adjuvant.
Division of Viral Pathogenesis, Harvard Medical School, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
D H
DH
Barouch
S
S
Santra
T D
TD
Steenbeke
X X
XX
Zheng
H C
HC
Perry
M E
ME
Davies
D C
DC
Freed
A
A
Craiu
T B
TB
Strom
J W
JW
Shiver
N L
NL
Letvin
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000276:Adjuvants, Immunologic / Q000008:administration & dosage* / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D016207:Cytokines / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics*; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology; D015497:HIV-1 / Q000276:immunology*; D007136:Immunoglobulins / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000494:pharmacology; D007273:Injections, Intramuscular; D007376:Interleukin-2 / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008969:Molecular Sequence Data; D010957:Plasmids / Q000008:administration & dosage / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000276:immunology; D012995:Solubility; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000276:immunology*
D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D016207:Cytokines; D015699:HIV Envelope Protein gp120; D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; D019444:Vaccines, DNA