Treatment with native heterodimeric IL-15 increases cytotoxic lymphocytes and reduces SHIV RNA in lymph nodes

PLoS Pathog. 2018 Feb 23;14(2):e1006902. doi: 10.1371/journal.ppat.1006902. eCollection 2018 Feb.

Abstract

B cell follicles in secondary lymphoid tissues represent an immune privileged sanctuary for AIDS viruses, in part because cytotoxic CD8+ T cells are mostly excluded from entering the follicles that harbor infected T follicular helper (TFH) cells. We studied the effects of native heterodimeric IL-15 (hetIL-15) treatment on uninfected rhesus macaques and on macaques that had spontaneously controlled SHIV infection to low levels of chronic viremia. hetIL-15 increased effector CD8+ T lymphocytes with high granzyme B content in blood, mucosal sites and lymph nodes, including virus-specific MHC-peptide tetramer+ CD8+ cells in LN. Following hetIL-15 treatment, multiplexed quantitative image analysis (histo-cytometry) of LN revealed increased numbers of granzyme B+ T cells in B cell follicles and SHIV RNA was decreased in plasma and in LN. Based on these properties, hetIL-15 shows promise as a potential component in combination immunotherapy regimens to target AIDS virus sanctuaries and reduce long-term viral reservoirs in HIV-1 infected individuals.

Trial registration: ClinicalTrials.gov NCT02452268.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / therapeutic use
  • Animals
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / pathology
  • Female
  • Germinal Center / drug effects
  • Germinal Center / pathology
  • Immunotherapy / methods
  • Interleukin-15 / chemistry
  • Interleukin-15 / metabolism
  • Interleukin-15 / therapeutic use*
  • Lymph Nodes / metabolism*
  • Lymph Nodes / pathology
  • Lymph Nodes / virology
  • Lymphocyte Count
  • Macaca mulatta
  • Male
  • Protein Multimerization
  • RNA, Viral / analysis
  • RNA, Viral / metabolism*
  • Simian Acquired Immunodeficiency Syndrome / drug therapy*
  • Simian Acquired Immunodeficiency Syndrome / immunology
  • Simian Acquired Immunodeficiency Syndrome / virology
  • Simian Immunodeficiency Virus / genetics*
  • Simian Immunodeficiency Virus / metabolism
  • T-Lymphocytes, Cytotoxic / drug effects*
  • T-Lymphocytes, Cytotoxic / pathology
  • T-Lymphocytes, Helper-Inducer / drug effects
  • T-Lymphocytes, Helper-Inducer / pathology

Substances

  • Adjuvants, Immunologic
  • Interleukin-15
  • RNA, Viral

Associated data

  • ClinicalTrials.gov/NCT02452268