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PMID: 9649576 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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.

The Journal of clinical investigation ·Vol. 102 ·No. 1 ·1998-07-01 ·Pages 223-31

Oliva A, Kinter AL, Vaccarezza M, Rubbert A, Catanzaro A, Moir S, Monaco J, Ehler L, Mizell S, Jackson R, Li Y, Romano JW, Fauci AS

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.

MeSH Terms
CD3 Complex/physiology CD8-Positive T-Lymphocytes/metabolism Chemokines, CC/biosynthesis,genetics,pharmacology HIV Infections/immunology,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
Chemicals
CD3 Complex Chemokines, CC Interleukin-15 Interleukin-2 RNA, Messenger Receptors, IgG Interleukin-12
Authors & Affiliations
13 authors, click to expand affiliations / ORCID
Oliva A
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. aoliva@atlas.niaid.nih.gov
Kinter A L
Vaccarezza M
Rubbert A
Catanzaro A
Moir S
Monaco J
Ehler L
Mizell S
Jackson R
Li Y
Romano J W
Fauci A S
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Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI2323
Email
aoliva@atlas.niaid.nih.gov
Published
1998-07-01
Pages
223-31
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC509084
Subset
IM
External Links
PubMed source DOI: 10.1172/JCI2323 PMC Full Text View journal details
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