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.
|Number of pages||9|
|Journal||Journal of Clinical Investigation|
|Publication status||Published - Jul 1 1998|
- Innate immunity
- NK cells
ASJC Scopus subject areas