Immunization with HIV-1 Gag protein conjugated to a TLR7/8 agonist results in the generation of HIV-1 Gag-specific Th1 and CD8+ T cell responses

J Immunol. 2005 Jun 15;174(12):7676-83. doi: 10.4049/jimmunol.174.12.7676.


One strategy to induce optimal cellular and humoral immune responses following immunization is to use vaccines or adjuvants that target dendritic cells and B cells. Activation of both cell types can be achieved using specific TLR ligands or agonists directed against their cognate receptor. In this study, we compared the ability of the TLR7/8 agonist R-848, which signals only via TLR7 in mice, with CpG oligodeoxynucleotides for their capacity to induce HIV-1 Gag-specific T cell and Ab responses when used as vaccine adjuvants with HIV-1 Gag protein in mice. Injection of R-848 and CpG oligodeoxynucleotides alone enhanced the innate immune responses in vivo as demonstrated by high serum levels of inflammatory cytokines, including IL-12p70 and IFN-alpha, and increased expression of CD80, CD86, and CD40 on CD11c(+) dendritic cells. By contrast, R-848 was a relatively poor adjuvant for inducing primary Th1 or CD8(+) T cell responses when administered with HIV-1 Gag protein. However, when a TLR7/8 agonist structurally and functionally similar to R-848 was conjugated to HIV-1 Gag protein both Th1 and CD8(+) T cells responses were elicited as determined by intracellular cytokine and tetramer staining. Moreover, within the population of HIV-1 Gag-specific CD8(+) CD62(low) cells, approximately 50% of cells expressed CD127, a marker shown to correlate with the capacity to develop into long-term memory cells. Overall, these data provide evidence that TLR7/8 agonists can be effective vaccine adjuvants for eliciting strong primary immune responses with a viral protein in vivo, provided vaccine delivery is optimized.

Publication types

  • Comparative Study

MeSH terms

  • AIDS Vaccines / administration & dosage
  • AIDS Vaccines / immunology*
  • Adjuvants, Immunologic / administration & dosage
  • Animals
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / virology
  • Cell Differentiation / immunology
  • CpG Islands / immunology
  • Cytokines / biosynthesis
  • Dendritic Cells / cytology
  • Dendritic Cells / immunology
  • Epitopes, T-Lymphocyte / administration & dosage
  • Epitopes, T-Lymphocyte / immunology*
  • Female
  • Gene Products, gag / administration & dosage
  • Gene Products, gag / immunology*
  • HIV-1 / immunology*
  • Imidazoles / administration & dosage
  • Imidazoles / immunology*
  • Immunoglobulin G / biosynthesis
  • Membrane Glycoproteins / agonists*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Oligodeoxyribonucleotides / administration & dosage
  • Oligodeoxyribonucleotides / immunology
  • Receptors, Cell Surface / agonists*
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Th1 Cells / virology
  • Toll-Like Receptor 7
  • Vaccines, Conjugate / administration & dosage
  • Vaccines, Conjugate / immunology


  • AIDS Vaccines
  • Adjuvants, Immunologic
  • CPG-oligonucleotide
  • Cytokines
  • Epitopes, T-Lymphocyte
  • Gene Products, gag
  • Imidazoles
  • Immunoglobulin G
  • Membrane Glycoproteins
  • Oligodeoxyribonucleotides
  • Receptors, Cell Surface
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • Vaccines, Conjugate
  • resiquimod