Oliva A, 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
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
J Clin Invest. 1998 Jul 1;102(1):223-31. doi: 10.1172/JCI2323.
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.
巨噬细胞炎性蛋白（MIP）-1α、MIP-1β和调节激活正常T细胞表达和分泌因子（RANTES）是CC趋化因子受体CCR5的天然配体，它们通过干扰MT-2阴性HIV-1毒株利用CCR5作为进入CD4(+)细胞的共受体的能力，来抑制这些毒株的复制。本研究调查了从HIV感染个体中分离出的自然杀伤（NK）细胞产生CC趋化因子的能力，以及在自体、内源性感染细胞中抑制HIV复制和阻断MT-2阴性HIV进入CD4(+) T细胞系PM-1的能力。从HIV感染个体中新鲜分离出的NK细胞含有大量MIP-1α和RANTES的mRNA拷贝。NK细胞组成性地产生大量RANTES、MIP-1α和MIP-1β，单独用IL-2刺激时以及在其进行特征性裂解活性（杀伤K562）时都会产生。CD16交联并用IL-2或IL-15刺激后，NK细胞产生CC趋化因子的水平与抗CD3刺激的CD8(+) T细胞产生的水平相当。此外，CD16交联的NK细胞在自体CD8/NK细胞耗竭的PBMC共培养物中抑制（49%-97%）病毒复制，其程度与PHA或抗CD3刺激的CD8(+) T细胞相似。在50%的受试患者中，针对MIP-1α、MIP-1β和RANTES的中和抗体可消除NK介导的HIV抑制作用；相反，中和CC趋化因子后，CD8(+) T细胞介导的抑制作用没有明显受到影响。用IL-2或IL-15刺激CD16交联的NK细胞培养物所得的上清液显著抑制MT-2阴性HIV毒株BaL进入CD4(+)CCR5(+) PM-1 T细胞系。这些数据表明，活化的NK细胞可能是体内CC趋化因子的重要来源，并且除了经典的NK介导的裂解机制外，还可能通过CC趋化因子介导的机制抑制HIV复制。
