Tilton John C, Johnson Alison J, Luskin Marlise R, Manion Maura M, Yang Jun, Adelsberger Joseph W, Lempicki Richard A, Hallahan Claire W, McLaughlin Mary, Mican Joann M, Metcalf Julia A, Iyasere Christiana, Connors Mark
Laboratory of Immunoregulation, National Institute of Allergy and Infectious Diseases/NIH, Bldg 10, Rm 11B-09, 10 Center Drive, Bethesda, MD 20892-1876, USA.
J Virol. 2006 Dec;80(23):11486-97. doi: 10.1128/JVI.00324-06. Epub 2006 Sep 27.
The effect of human immunodeficiency virus (HIV) infection and high-level HIV replication on the function of monocytes was investigated. HIV-positive patients had elevated levels of spontaneous production of some or all of the monocyte proinflammatory cytokines measured (interleukin-1beta [IL-1beta], IL-6, and tumor necrosis factor alpha [TNF-alpha]) compared to uninfected controls. In patients on therapy with high frequencies of monocytes producing proinflammatory cytokines, this frequency was diminished in the context of viremia during an interruption of therapy. Diminished production of proinflammatory cytokines during viremia was restored by culture with autologous CD4(+) T cells or monocytes from an on-therapy time point or lipopolysaccharide (LPS). Microarray analysis demonstrated that diminished monocyte production of proinflammatory cytokines was correlated with elevated type I interferon-stimulated gene transcripts. The addition of exogenous alpha 2A interferon diminished the spontaneous production of IL-1beta, IL-6, and TNF-alpha but did not affect responses to LPS, recapitulating the changes observed for HIV-viremic patients. These results suggest that monocyte function is diminished during high-level HIV viremia and that this effect is mediated by chronic stimulation by type I interferons. This effect on monocytes during viremia may play a role in diminished innate or adaptive immune system functions in HIV-infected patients. In addition, the restoration of these functions may also play a role in some immune reconstitution syndromes observed during initiation of therapy.
研究了人类免疫缺陷病毒（HIV）感染及高水平HIV复制对单核细胞功能的影响。与未感染的对照组相比，HIV阳性患者某些或所有所检测的单核细胞促炎细胞因子（白细胞介素-1β [IL-1β]、IL-6和肿瘤坏死因子α [TNF-α]）的自发产生水平升高。在接受治疗的患者中，产生促炎细胞因子的单核细胞频率较高，在治疗中断期间病毒血症的情况下，该频率会降低。病毒血症期间促炎细胞因子产生的减少可通过与来自治疗期时间点的自体CD4(+) T细胞或单核细胞或脂多糖（LPS）培养来恢复。微阵列分析表明，单核细胞促炎细胞因子产生的减少与I型干扰素刺激基因转录本的升高相关。添加外源性α2A干扰素可减少IL-1β、IL-6和TNF-α的自发产生，但不影响对LPS的反应，这重现了在HIV病毒血症患者中观察到的变化。这些结果表明，在高水平HIV病毒血症期间单核细胞功能会降低，且这种效应是由I型干扰素的慢性刺激介导的。病毒血症期间对单核细胞的这种影响可能在HIV感染患者的固有或适应性免疫系统功能降低中起作用。此外，这些功能的恢复也可能在治疗开始时观察到的一些免疫重建综合征中起作用。
