title: 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.
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.
authors.affiliation: Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. aoliva@atlas.niaid.nih.gov
authors.forename: A
authors.initials: A
authors.lastname: Oliva
authors.forename: A L
authors.initials: AL
authors.lastname: Kinter
authors.forename: M
authors.initials: M
authors.lastname: Vaccarezza
authors.forename: A
authors.initials: A
authors.lastname: Rubbert
authors.forename: A
authors.initials: A
authors.lastname: Catanzaro
authors.forename: S
authors.initials: S
authors.lastname: Moir
authors.forename: J
authors.initials: J
authors.lastname: Monaco
authors.forename: L
authors.initials: L
authors.lastname: Ehler
authors.forename: S
authors.initials: S
authors.lastname: Mizell
authors.forename: R
authors.initials: R
authors.lastname: Jackson
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: J W
authors.initials: JW
authors.lastname: Romano
authors.forename: A S
authors.initials: AS
authors.lastname: Fauci
mesh_terms: D017252:CD3 Complex / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D019742:Chemokines, CC / Q000096:biosynthesis* / Q000235:genetics / Q000494:pharmacology; D015658:HIV Infections / Q000276:immunology* / Q000821:virology; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D018664:Interleukin-12 / Q000494:pharmacology; D019409:Interleukin-15 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007694:Killer Cells, Natural / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D017452:Receptors, IgG / Q000502:physiology; D014779:Virus Replication
chemical_list: D017252:CD3 Complex; D019742:Chemokines, CC; D019409:Interleukin-15; D007376:Interleukin-2; D012333:RNA, Messenger; D017452:Receptors, IgG; D018664:Interleukin-12