Development of HSV-specific CD4+ Th1 responses and CD8+ cytotoxic T lymphocytes with antiviral activity by vaccination with the HSV-2 mutant ICP10DeltaPK

Vaccine. 2002 Jun 21;20(21-22):2796-807. doi: 10.1016/s0264-410x(02)00199-8.

Abstract

A growth compromised herpes simplex virus type 2 (HSV-2) mutant which is deleted in the PK domain of the large subunit of ribonucleotide reductase (ICP10DeltaPK) protects from HSV-2 challenge in the mouse and guinea pig cutaneous and vaginal models and reduces the incidence and frequency of recurrent disease (Vaccine (17) (1999) 1951; Vaccine (19) (2001) 1879). The present studies were designed to identify the immune responses induced by ICP10DeltaPK and define the component responsible for protective activity. We found that ICP10DeltaPK elicits a predominant HSV-specific T helper type 1 (Th1) response, as evidenced by: (1) higher levels of HSV-specific IgG2a (Th1) than IgG1 (Th2) isotypes and (2) higher numbers of CD4+ IFN-gamma than IL-10 secreting T cells in popliteal lymph nodes. This Th1 response pattern was associated with a significant increase in the levels of IL-12 produced by dendritic cells from ICP10DeltaPK than HSV-2 immunized animals. Lymph node cells (LNCs) from ICP10DeltaPK immunized mice had significantly higher levels of HSV-2 specific cytolytic activity than LNCs from mice immunized with HSV-2 and it was mediated by CD8+ T cells. CD8+ CTL were not seen in LNCs from HSV-2 immunized mice. In adoptive transfer experiments, CD8+ T cells and, to a lower extent, CD4+ T cells from ICP10DeltaPK immunized mice inhibited HSV-2 replication, suggesting that they are involved in the protective immunity induced by ICP10DeltaPK vaccination.

MeSH terms

  • Animals
  • Antibodies, Viral / analysis
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / immunology
  • Chlorocebus aethiops
  • Defective Viruses / enzymology
  • Defective Viruses / genetics
  • Defective Viruses / growth & development
  • Defective Viruses / immunology
  • Disease Models, Animal
  • Enzyme-Linked Immunosorbent Assay
  • Herpes Genitalis / immunology
  • Herpes Genitalis / prevention & control
  • Herpes Genitalis / therapy*
  • Herpesvirus 2, Human / genetics
  • Herpesvirus 2, Human / growth & development
  • Herpesvirus 2, Human / immunology*
  • Immunization
  • Immunologic Memory
  • Interleukin-12 / metabolism
  • Mice
  • Mice, Inbred BALB C
  • Mutation
  • Protein-Serine-Threonine Kinases / immunology
  • Ribonucleotide Reductases / immunology
  • T-Lymphocytes, Cytotoxic / immunology*
  • Th1 Cells / immunology*
  • Vero Cells
  • Viral Vaccines / immunology*
  • Viral Vaccines / pharmacology*
  • Viral Vaccines / therapeutic use

Substances

  • Antibodies, Viral
  • Viral Vaccines
  • Interleukin-12
  • ICP10 protein, herpes simplex virus type 2
  • Ribonucleotide Reductases
  • Protein-Serine-Threonine Kinases