Natural Killer Cells From Human Immunodeficiency Virus (HIV)-infected Individuals Are an Important Source of CC-chemokines and Suppress HIV-1 Entry and Replication in Vitro

J Clin Invest. 1998 Jul 1;102(1):223-31. doi: 10.1172/JCI2323.

Abstract

Macrophage inflammatory protein (MIP)-1alpha, MIP-1beta, and RANTES (regulated on activation, normal T cell expressed and secreted), which are the natural ligands of the CC-chemokine receptor CCR5, inhibit replication of MT-2- negative strains of HIV-1 by interfering with the ability of these strains to utilize CCR5 as a coreceptor for entry in CD4(+) cells. The present study investigates the capacity of natural killer (NK) cells isolated from HIV-infected individuals to produce CC-chemokines and to suppress HIV replication in autologous, endogenously infected cells as well as to block entry of MT-2-negative HIV into the CD4(+) T cell line PM-1. NK cells freshly isolated from HIV-infected individuals had a high number of mRNA copies for MIP-1alpha and RANTES. NK cells produced significant amounts of RANTES, MIP-1alpha, and MIP-1beta constitutively, in response to stimulation with IL-2 alone and when they were performing their characteristic lytic activity (K562 killing). After CD16 cross-linking and stimulation with IL-2 or IL-15 NK cells produced CC-chemokines to levels comparable to those produced by anti-CD3-stimulated CD8(+) T cells. Furthermore, CD16 cross-linked NK cells suppressed (49-97%) viral replication in cocultures of autologous CD8/NK-depleted PBMC to a degree similar to that of PHA or anti-CD3-stimulated CD8(+) T cells. In 50% of patients tested, NK-mediated HIV suppression could be abrogated by neutralizing antibodies to MIP-1alpha, MIP-1beta and RANTES; in contrast, CD8(+) T cell-mediated suppression was not significantly overcome upon neutralization of CC-chemokines. Supernatants derived from cultures of CD16 cross-linked NK cells stimulated with IL-2 or IL-15 dramatically inhibited entry of a MT-2-negative strain of HIV, BaL, in the CD4(+)CCR5(+) PM-1 T cell line. These data suggest that activated NK cells may be an important source of CC-chemokines in vivo and may suppress HIV replication by CC-chemokine-mediated mechanisms in addition to classic NK-mediated lytic mechanisms.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • CD3 Complex / physiology
  • CD8-Positive T-Lymphocytes / metabolism
  • Chemokines, CC / biosynthesis*
  • Chemokines, CC / genetics
  • Chemokines, CC / pharmacology
  • HIV Infections / immunology*
  • HIV Infections / virology
  • HIV-1 / physiology*
  • Humans
  • Interleukin-12 / pharmacology
  • Interleukin-15 / pharmacology
  • Interleukin-2 / pharmacology
  • Killer Cells, Natural / physiology*
  • RNA, Messenger / analysis
  • Receptors, IgG / physiology
  • Virus Replication*

Substances

  • CD3 Complex
  • Chemokines, CC
  • Interleukin-15
  • Interleukin-2
  • RNA, Messenger
  • Receptors, IgG
  • Interleukin-12