NATURAL-KILLER-CELLS FROM HUMAN-IMMUNODEFICIENCY-VIRUS (HIV)-INFECTEDINDIVIDUALS ARE AN IMPORTANT SOURCE OF CC-CHEMOKINES AND SUPPRESS HIV-1 ENTRY AND REPLICATION IN-VITRO

Macrophage inflammatory protein (MIP)-1 alpha, MIP-1 beta, and RANTES (regulated on activation, normal T cell expressed and secreted), which are the natural ligands of the CC-chemokine receptor CCR5, inhibit re plication of MT-2-negative strains of HIV-1 by interfering with the ab ility of these strains to utilize CCR5 as a coreceptor for entry in CD 4(+) cells. The present study investigates the capacity of natural kil ler (NK) cells isolated from HIV-infected individuals to produce CC-ch emokines and to suppress HIV replication in autologous, endogenously i nfected 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 i ndividuals had a high number of mRNA copies for MIP-1 alpha and RANTES . NK cells produced significant amounts of RANTES, MIP-1 alpha, and MI P-1 beta constitutively, in response to stimulation with IL-2 alone an d 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 autol ogous 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 HI V suppression could be abrogated by neutralizing antibodies to MIP-1 a lpha, MIP-1 beta and RANTES; in contrast, CD8+ T cell-mediated suppres sion was not significantly overcome upon neutralization of CC-chemokin es. Supernatants derived from cultures of CD16 cross-linked NK cells s timulated with IL-2 or IL-15 dramatically inhibited entry of a MT-2-ne gative strain of HIV, Bat, in the CD4(+)CCR5(+) PM-1 T cell line. Thes e data suggest that activated NK cells may be an important source of C C-chemokines in vivo and may suppress HIV replication by CC-chemokine- mediated mechanisms in addition to classic NK-mediated lytic mechanism s.