Hemin activation ameliorates HIV-1 infection via heme oxygenase-1 induction
Hemin activation ameliorates HIV-1 infection via heme oxygenase-1 induction
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DOI：
10.4049/jimmunol.176.7.4252
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发表时间：
2006-04-01
影响因子：
4.4
通讯作者：
Dhawan, Subhash
中科院分区：
文献类型：
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作者：
Devadas, Krishnakumar;Dhawan, Subhash
氯化血红素是血红蛋白的重要组成部分，是食品和药物管理局批准用于治疗急性卟啉病的生物治疗剂的活性成分。本报告描述了该分子通过血红素加氧酶-1（HO-1）诱导宿主防御HIV-1感染的生物学功能。用氯化血红素处理单核细胞实质上抑制HIV复制，这通过几乎检测不到的病毒RNA和无细胞HIV-1 p24蛋白以剂量依赖性方式证明。在感染前、感染时或感染后暴露于这些细胞的氯化血红素导致HIV DNA减少> 90%，HIV-1 p24水平和HIV相关的细胞病变效应显著降低。此外，氯化血红素治疗显着抑制单核细胞和T细胞接种R5，X4，R5 X4嗜性菌株，逆转录酶耐药，叠氮胸苷耐药，ddC/ddI耐药，耐尼韦拉平，和其他临床HIV分离株的感染。在HIV感染后4天腹膜内施用氯化血红素使人PBMC重建的非肥胖糖尿病SCID小鼠血清中的病毒载量降低> 6倍。抑制HIV复制在氯化血红素激活的细胞与HO-1的诱导，并减弱锡原卟啉（SnPP）IX，HO-1活性的抑制剂，这表明一个关键的作用，这种内源性酶在调节HIV感染。在CCR-5、CXCR-4和CD 4共表达GHOST（3）细胞中，氯化血红素诱导的HO-1诱导与Tat依赖性激活长末端重复启动子的抑制一致，导致GFP表达减少。这些发现表明，氯化血红素诱导的HO-1活性作为宿主防御机制对HIV-1感染的重要作用。
Hemin, a critical component of hemoglobin, is an active ingredient of a biologic therapeutic approved by the Food and Drug Administration for the treatment of acute porphyries. This report describes a biological function of this molecule in inducing host defense against HIV-1 infection via heme oxygenase-1 (HO-1) induction. Treatment of monocytes with hemin substantially inhibited HIV replication, as evident by nearly undetectable viral RNA and cell-free HIV-1 p24 protein in a dose-dependent manner. Hemin exposure of these cells before infection, at the time of infection, or after infection caused > 90% reduction of HIV DNA with substantially low levels of HIV-1 p24 and HIV-associated cytopathic effects. In addition, hemin treatment significantly suppressed infection of both monocytes and T cells inoculated with R5, X4, R5X4 tropic strains, and reverse transcriptase-resistant, azidothymidine-resistant, ddC/ddI-resistant, nivirapine-resistant, and other clinical HIV isolates. Intraperitoneal administration of hemin 4 days after HIV infection reduced viral load in the serum of human PBMC-reconstituted nonobese diabetic SCID mice by > 6-fold. Suppression of HIV replication in hemin-activated cells correlated with the induction of HO-1 and was attenuated by tin protoporphyrin (SnPP) IX, an inhibitor of HO-1 activity, suggesting a pivotal role of this endogenous enzyme in the regulation of HIV infection. Hemin-induced HO-1 induction in the CCR-5, CXCR-4, and CD4 coexpressing GHOST(3) cells was consistent with the inhibition of Tat-dependent activation of long terminal repeat promoter leading to reduced GFP expression. These findings suggest an important role of hemin-induced HO-1 activity as a host defense mechanism against HIV-1 infection.