Mechanisms for macrophage-mediated HIV-1 induction
Mechanisms for macrophage-mediated HIV-1 induction
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DOI：
10.4049/jimmunol.173.11.6735
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发表时间：
2004-12-01
影响因子：
4.4
通讯作者：
Dhawan, S
中科院分区：
文献类型：
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作者：
Devadas, K;Hardegen, NJ;Dhawan, S
病毒潜伏期是HIV-1感染患者的一种长期致病状态。慢性感染细胞中的低但持续的病毒复制可以通过用促炎细胞因子如TNF-α、IL-1 β或其他宿主因子刺激来激活。然而，细胞激活诱导的确切机制。潜伏感染的细胞产生病毒体仍然不清楚。在本报告中，我们提出的证据表明，在潜伏感染的U1或ACH 2细胞的人巨噬细胞的HIV-1复制的激活介导的NF-κ B p50/p65二聚体的快速核定位伴随促炎细胞因子的表达增加。从巨噬细胞和U1和ACH 2细胞的共培养物中分离的mRNA的多重RT-PCR扩增显示在共孵育3小时内显著诱导IL-1 β、IL-6、IL-8、TNF-α和TGF-β表达。在共培养前用多聚甲醛固定巨噬细胞、U-1或ACH 2细胞完全消除了NF-κ B亚基和HIV-1复制的诱导，这表明两种细胞类型之间的合作相互作用是细胞活化的重要过程。用中和性抗TNF-α抗体预处理巨噬细胞-U1或巨噬细胞-ACH 2共培养物可下调HIV-1的复制。此外，用NF-κ B抑制剂（E）3-[（4-甲基苯基）磺酰基]-2-丙烯腈（BAY 11-7082）预处理巨噬细胞-U1或巨噬细胞-ACH 2共培养物可阻止细胞因子表达的诱导，表明NF-κ B介导的信号传导在巨噬细胞重新激活潜伏感染细胞中的HIV-1中发挥关键作用。这些结果提供了巨噬细胞诱导潜伏感染细胞中HIV-1复制的机制。
Viral latency is a long-term pathogenic condition in patients infected with HIV-1. Low but sustained virus replication in chronically infected cells can be activated by stimulation with proinflammatory cytokines such as TNF-alpha, IL-1 beta, or other host factors. However, the precise mechanism by which cellular activation induces. latently infected cells to produce virions has remained unclear. In the present report, we present evidence that activation of HIV-1 replication in latently infected U1 or ACH2 cells by human macrophages is mediated by a rapid nuclear localization of NF-kappaB p50/p65 dimer with concomitant increased expression of proinflammatory cytokines. Multiplexed RT-PCR amplification of mRNA isolated from cocultures of macrophages and U1 and ACH2 cells showed significant induction of IL-1beta, IL-6, IL-8, TNF-alpha, and TGF-beta expression within 3 h of coincubation. Fixation of macrophages, U-1, or ACH2 cells with paraformaldehyde before coculture completely abrogated the induction of NF-kappaB subunits and HIV-1 replication, suggesting that cooperative interaction between the two cell types is an essential process for cellular activation. Pretreatment of macrophage-U1 or macrophage-ACH2 cocultures with neutralizing anti-TNF-alpha Ab down-regulated the replication of HIV-1. In addition, pretreatment of macrophage-U1 or macrophage-ACH2 cocultures with the NF-kappaB inhibitor (E)3-[(4-methylphenyl)sulfonyl]-2-propenenitrile (BAY 11-7082) prevented the induction of cytokine expression, indicating a pivotal role of NF-kappaB-mediated signaling in the reactivation of HIV-1 in latently infected cells by macrophages. These results provide a mechanism by which macrophages induce HIV-1 replication in latently infected cells.