Purified herpes simplex type 1 glycoprotein D (gD) genetically fused with the type 16 human papillomavirus E7 oncoprotein enhances antigen-specific CD8+ T cell responses and confers protective antitumor immunity

Mol Pharm. 2011 Dec 5;8(6):2320-30. doi: 10.1021/mp200194s. Epub 2011 Oct 19.

Abstract

Type 1 herpes virus (HSV-1) glycoprotein D (gD) enhances antigen-specific immune responses, particularly CD8(+) T cell responses, in mice immunized with DNA vaccines encoding hybrid proteins genetically fused with the target antigen at a site near the C-terminal end. These effects are attributed to the interaction of gD with the herpes virus entry mediator (HVEM) and the concomitant blockade of a coinhibitory mechanism mediated by the B- and T-lymphocyte attenuator (BTLA). However, questions concerning the requirement for endogenous synthesis of the antigen or the adjuvant/antigen fusion itself have not been addressed so far. In the present study, we investigated these points using purified recombinant gDs, genetically fused or not with type 16 papilloma virus (HPV-16) E7 oncoprotein. Soluble recombinant gDs, but not denatured forms, retained the ability to bind surface-exposed cellular receptors of HVEM-expressing U937 cells. In addition, in vivo administration of the recombinant proteins, particularly gD genetically fused with E7 (gDE7), promoted the activation of dendritic cells (DC) and antigen-specific cytotoxic CD8(+) T cells. More relevantly, mice immunized with the gDE7 protein developed complete preventive and partial therapeutic antitumor protection, as measured in mice following the implantation of TC-1 cells expressing HPV-16 oncoproteins. Collectively, these results demonstrate that the T cell adjuvant effects of the HSV-1 gD protein did not require endogenous synthesis and could be demonstrated in mice immunized with purified recombinant proteins.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • CD8 Antigens / metabolism
  • Herpesvirus 1, Human*
  • Human papillomavirus 16*
  • Mice
  • Mice, Inbred C57BL
  • Papillomavirus E7 Proteins / genetics*
  • Papillomavirus E7 Proteins / immunology
  • Papillomavirus E7 Proteins / pharmacology*
  • Recombinant Proteins / genetics
  • Recombinant Proteins / pharmacology
  • T-Lymphocytes / drug effects*
  • T-Lymphocytes / immunology
  • Vaccines, DNA / immunology*
  • Viral Envelope Proteins / genetics*
  • Viral Envelope Proteins / pharmacology

Substances

  • Antineoplastic Agents
  • CD8 Antigens
  • Papillomavirus E7 Proteins
  • Recombinant Proteins
  • Vaccines, DNA
  • Viral Envelope Proteins
  • glycoprotein D, Human herpesvirus 1
  • oncogene protein E7, Human papillomavirus type 16