Adenovirus 5- and 35-based immunotherapy enhances the strength but not breadth or quality of immunity during chronic SIV infection

Eur J Immunol. 2009 Sep;39(9):2437-49. doi: 10.1002/eji.200839130.

Abstract

Heterologous adenovirus-based vectors hold promise as preventative HIV vaccines but their capacity to induce effective T-cell immunity in established infection has not been explored. We vaccinated rhesus macaques chronically infected with SIVmac251 and undergoing antiretroviral therapy (ART) with human adenovirus serotype 5-based vectors expressing SIV Gag, Env, and Nef with and without IL-15 and evaluated vaccine immunogenicity. Vaccination increased Ag-specific T cells 20-fold but did not expand the breadth of epitopes recognized or the quality of response, as the majority of CD8(+) and CD4(+) T cells produced only one cytokine irrespective of vaccination. Immunization transiently restored blood CD4(+) central memory T cells (Tcm) and boosted CD4(+) and CD8(+) Tcm and effector cell responses but did not prevent virus rebound upon cessation of ART. Boosting with human adenovirus serotype 35-based vectors during a second ART cycle increased Ag-specific T cells to 50-fold above pre-vaccination levels and boosted CD4(+) Tcm numbers but did not expand the breadth or quality of immunity or control virus levels following drug discontinuation. The number of blood CD4(+) Tcm correlated positively with complexity of T-cell responses and negatively with virus load, suggesting that more complete restoration of this subset through vaccination would be beneficial.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenoviruses, Human*
  • Animals
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / virology
  • CD8-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / virology
  • Chronic Disease
  • Cytokines / immunology
  • Cytokines / metabolism
  • Gene Products, env / genetics
  • Gene Products, env / immunology
  • Gene Products, gag / genetics
  • Gene Products, gag / immunology
  • Genetic Vectors
  • Humans
  • Immunotherapy, Active / methods*
  • Interleukin-15 / immunology*
  • Interleukin-15 / metabolism
  • Macaca mulatta
  • SAIDS Vaccines / genetics
  • SAIDS Vaccines / therapeutic use*
  • Simian Acquired Immunodeficiency Syndrome / therapy*
  • Simian Immunodeficiency Virus / immunology
  • Viral Regulatory and Accessory Proteins / genetics
  • Viral Regulatory and Accessory Proteins / immunology

Substances

  • Cytokines
  • Gene Products, env
  • Gene Products, gag
  • Interleukin-15
  • NEF protein, SIV
  • SAIDS Vaccines
  • Viral Regulatory and Accessory Proteins