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7 Potent CD4+ T-Cell Responses Elicited by a Dicistronic HIV-1 DNA Vaccine Expressing gp120 and GM-CSF
S. Santra*1, D. H. Barouch1, K. Tenner-Racz2, P. Racz2, M. J. Kuroda1, J. E. Schmitz1, S. S. Jackson1, M. A. Lifton1, D. C. Freed3, H. C. Perry3, M.-E. Davies3, J. W. Shiver3, and N. L. Letvin1.
1Beth Israel Deaconess Med. Ctr., Harvard Med. Sch., Boston, MA, USA; 2Bernhard-Nocht-Inst. for Tropical Med., Hamburg, Germany; and 3Merck Res. Labs, West Point, PA, USA
Background: Virus-specific CD4+ T-cell responses have been shown to be important in controlling HIV-1 replication. Vigorous CD4+ T-cell proliferative responses have been detected in long-term nonprogressors and in individuals following treatment of acute HIV-1 infection. Therefore, candidate HIV-1 vaccines should elicit potent CD4+ as well as CD8+ T-cell responses.
Methods: Mice were immunized with plasmids expressing GM-CSF and HIV-1 gp120 or with a dicistronic plasmid expressing both HIV-1 gp120 and GM-CSF. Splenocytes of the mice were assessed for proliferative responses, cytotoxicity, and IFN-gamma secretion.
Results: 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 of mice with a dicistronic plasmid that coexpressed gp120 and GM-CSF under the control of a single promoter dramatically augmented the 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 antibody and CD8+ T-cell responses were not significantly augmented by the addition of GM-CSF. A 100-fold lower dose of the gp120/GM-CSF dicistronic DNA vaccine was required for eliciting detectable gp120-specific splenocyte proliferative responses as compared with the monocistronic gp120 DNA vaccine. Consistent with these findings, I.M. injection of the gp120/GM-CSF dicistronic DNA vaccine resulted in a more extensive cellular infiltrate at the site of inoculation than the monocistronic gp120 DNA vaccine.
Conclusions: These results demonstrate that dicistronic DNA vaccines containing GM-CSF elicit remarkably potent CD4+ T-cell responses and suggest that optimal helper T-cell priming requires coordinate expression of antigen and GM-CSF.
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