IL-15 treatment during acute simian immunodeficiency virus (SIV) infection increases viral set point and accelerates disease progression despite the induction of stronger SIV-specific CD8+ T cell responses

J Immunol. 2008 Jan 1;180(1):350-60. doi: 10.4049/jimmunol.180.1.350.

Abstract

In this study, we examined the effect of in vivo treatment of acutely SIV-infected Mamu-A*01+ rhesus macaques with IL-15. IL-15 treatment during acute infection increased viral set point by 3 logs and accelerated the development of simian AIDS in two of six animals with one developing early minimal lesion SIV meningoencephalitis. Although IL-15 induced a 2- to 3-fold increase in SIV-specific CD8+ T cell and NK cell numbers at peak viremia and reduced lymph node (LN) SIV-infected cells, this had no impact on peak viremia and did not lower viral set point. At viral set point, however, activated SIV-specific CD8+ T cells and NK cells were reduced in the blood of IL-15-treated animals and LN SIV-infected cells were increased. Week 30 LN from IL-15-treated animals had significantly increased Gag-specific CD8+ T cell numbers, whereas total cell, lymphocyte, and CD4+ T cell numbers were reduced. IL-15 treatment significantly reduced anti-SIV Ab concentrations at week 3 and viral set point. IL-15 increased Ki-67+CD4+ T cells at week 1 of treatment and reduced blood CCR5+ and CD45RA-CD62L- CD4+ T cells. The frequency of day 7 Ki-67+CD4+ T cells strongly correlated with viral set point. These findings suggest that CD4+ T cell activation during acute infection determines subsequent viral set point and IL-15 treatment by increasing such activation elevates viral set point. Finally, IL-15-treated acutely SIV-infected primates may serve as a useful model to investigate the poorly understood mechanisms that control viral set point and disease progression in HIV infection.

Publication types

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

MeSH terms

  • Animals
  • Antibodies, Viral / blood
  • CD3 Complex / analysis
  • CD4 Antigens / analysis
  • CD4-Positive T-Lymphocytes / immunology
  • CD8-Positive T-Lymphocytes / drug effects*
  • CD8-Positive T-Lymphocytes / immunology
  • Disease Models, Animal
  • Disease Progression
  • Gene Products, gag / analysis
  • Interleukin-15 / pharmacology*
  • Ki-67 Antigen / analysis
  • Killer Cells, Natural / immunology
  • Leukocyte Common Antigens / analysis
  • Lymph Nodes / immunology
  • Lymph Nodes / virology
  • Lymphocyte Activation / drug effects
  • Macaca mulatta*
  • Meningoencephalitis / immunology
  • Meningoencephalitis / pathology
  • Meningoencephalitis / virology
  • Receptors, CCR5 / analysis
  • Simian Acquired Immunodeficiency Syndrome / immunology*
  • Simian Acquired Immunodeficiency Syndrome / virology*
  • Simian Immunodeficiency Virus / drug effects*
  • Simian Immunodeficiency Virus / physiology
  • Viral Load
  • Viremia / immunology
  • Viremia / virology
  • Virus Replication*

Substances

  • Antibodies, Viral
  • CD3 Complex
  • CD4 Antigens
  • Gene Products, gag
  • Interleukin-15
  • Ki-67 Antigen
  • Receptors, CCR5
  • Leukocyte Common Antigens