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

Alessandra Oliva, Audrey L. Kinter, Mauro Vaccarezza, Andrea Rubbert, Andrew Catanzaro, Susan Moir, JoAn Monaco, Linda Ehler, Stephanie Mizell, Robert Jackson, Yuexia Li, Joseph W. Romano, Anthony S. Fauci

Research output: Contribution to journalArticlepeer-review

Abstract

Macrophage inflammatory protein (MIP)-1α, MIP-1β, 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-1α and RANTES. NK cells produced significant amounts of RANTES, MIP- 1α, and MIP-1β 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-1α, MIP-1β 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.

Original languageEnglish
Pages (from-to)223-231
Number of pages9
JournalJournal of Clinical Investigation
Volume102
Issue number1
Publication statusPublished - Jul 1 1998

Keywords

  • Chemokines
  • HIV
  • Human
  • Innate immunity
  • NK cells

ASJC Scopus subject areas

  • Medicine(all)

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