Potent CD4+ T cell responses elicited by a bicistronic HIV-1 DNA vaccine expressing gp120 and GM-CSF.
Virus-specific CD4(+) T cell responses have been shown to play a critical role in controlling HIV-1 replication. Candidate HIV-1 vaccines should therefore elicit potent CD4(+) as well as CD8(+) T cell responses. In this report we investigate the ability of plasmid GM-CSF to augment CD4(+) T cell responses elicited by an HIV-1 gp120 DNA vaccine in mice. Coadministration of a plasmid expressing GM-CSF with the gp120 DNA vaccine led to only a marginal increase in gp120-specific splenocyte CD4(+) T cell responses. However, immunization with a bicistronic plasmid that coexpressed gp120 and GM-CSF under control of a single promoter led to a dramatic augmentation of vaccine-elicited CD4(+) T cell responses, as measured by both cellular proliferation and ELISPOT assays. This augmentation of CD4(+) T cell responses was selective, since vaccine-elicited Ab and CD8(+) T cell responses were not significantly changed by the addition of GM-CSF. A 100-fold lower dose of the gp120/GM-CSF bicistronic DNA vaccine was required to elicit detectable gp120-specific splenocyte proliferative responses compared with the monocistronic gp120 DNA vaccine. Consistent with these findings, i.m. injection of the gp120/GM-CSF bicistronic DNA vaccine evoked a more extensive cellular infiltrate at the site of inoculation than the monocistronic gp120 DNA vaccine. These results demonstrate that bicistronic DNA vaccines containing GM-CSF elicit remarkably potent CD4(+) T cell responses and suggest that optimal Th cell priming requires the precise temporal and spatial codelivery of Ag and GM-CSF.
Barouch
Dan H
DH
Beth Israel Deaconess Medical Center, Boston, MA 02215, USA. dan_barouch@hotmail.com
Santra
Sampa
S
Tenner-Racz
Klara
K
Racz
Paul
P
Kuroda
Marcelo J
MJ
Schmitz
Joern E
JE
Jackson
Shawn S
SS
Lifton
Michelle A
MA
Freed
Dan C
DC
Perry
Helen C
HC
Davies
Mary-Ellen
ME
Shiver
John W
JW
Letvin
Norman L
NL
D016915:AIDS Vaccines / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology; D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000235:genetics; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D015967:Gene Expression Regulation, Viral / Q000276:immunology; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D015699:HIV Envelope Protein gp120 / Q000008:administration & dosage / Q000096:biosynthesis / Q000235:genetics* / Q000276:immunology; D015497:HIV-1 / Q000235:genetics* / Q000276:immunology; D007273:Injections, Intramuscular; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D018482:Muscle, Skeletal / Q000276:immunology / Q000473:pathology; D010957:Plasmids / Q000008:administration & dosage / Q000276:immunology; D019444:Vaccines, DNA / Q000008:administration & dosage / Q000235:genetics* / Q000276:immunology
D016915:AIDS Vaccines; D000276:Adjuvants, Immunologic; D015699:HIV Envelope Protein gp120; D019444:Vaccines, DNA; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor