Human Galectin-9 Is a Potent Mediator of HIV Transcription and Reactivation.
Human Galectin-9 Is a Potent Mediator of HIV Transcription and Reactivation.
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DOI：
10.1371/journal.ppat.1005677
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发表时间：
2016-06
期刊：
影响因子：
6.7
通讯作者：
Pillai SK
中科院分区：
文献类型：
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作者：
Abdel-Mohsen M;Chavez L;Tandon R;Chew GM;Deng X;Danesh A;Keating S;Lanteri M;Samuels ML;Hoh R;Sacha JB;Norris PJ;Niki T;Shikuma CM;Hirashima M;Deeks SG;Ndhlovu LC;Pillai SK
确定控制体内HIV转录、潜伏期和感染性的宿主免疫决定因素对于开发HIV治愈方法至关重要。基于我们最近发现宿主因子p21在抗逆转录病毒治疗（ART）过程中调节HIV转录，以及已发表的数据表明人类碳水化合物结合免疫调节蛋白半乳糖凝集素-9调节p21，我们假设半乳糖凝集素-9调节HIV转录。我们报告，在J-Lat HIV潜伏期模型中，给予重组的稳定形式的半乳糖凝集素-9（rGal-9）在体外有效逆转HIV潜伏期。此外，rGal-9在来自HIV感染的ART抑制个体的原代CD 4 + T细胞中离体逆转HIV潜伏期（p = 0.002），比伏立诺他（p = 0.02）更有效。rGal-9与潜伏期逆转剂“JQ 1”（一种布罗莫结构域抑制剂）共同施用表现出协同活性（p<0.05）。rGal-9通过T细胞表面上的N-连接寡糖和O-连接六糖发出信号，调节关键转录起始、启动子近端暂停和调节HIV潜伏期的染色质重塑因子的基因表达水平。除了潜伏的病毒再活化之外，rGal-9在体外和离体诱导宿主抗病毒脱氨酶APOBEC 3G的稳健表达（FDR<0.006），并显著降低子代病毒的感染性，降低了当治疗性逆转潜伏期时HIV储库将被补充的可能性。最后，72名HIV感染ART抑制个体血浆中可溶性半乳糖凝集素-9的内源性水平与CD 4 + T细胞中HIV RNA水平（p<0.02）以及循环抗HIV抗体的数量和结合亲和力（p<0.009）相关，表明半乳糖凝集素-9在治疗期间调节体内HIV转录和病毒产生中的作用。我们的数据表明，半乳糖凝集素-9和宿主糖基化机制应作为新的HIV治疗策略的基础进行探索。虽然抗逆转录病毒疗法（ART）已显着降低与HIV感染相关的发病率和死亡率，但由于治疗期间HIV潜伏感染细胞的持续存在，无法治愈。确定主要的宿主免疫决定因素，艾滋病毒的转录，潜伏期和感染性在体内将是一个关键的一步，在发展一个有效的治疗策略，艾滋病毒感染。在这项研究中，我们证明，人类免疫调节性碳水化合物结合蛋白半乳糖凝集素-9是HIV感染的个体对抑制性ART的HIV潜伏期的决定因素。半乳糖凝集素-9的管理有效地重新激活潜伏的HIV在CD 4 + T细胞离体，通过特定的聚糖在细胞表面上的信号传导，以调节基因表达水平的关键宿主因子，调节HIV转录。此外，半乳糖凝集素-9诱导宿主APOBEC 3蛋白，其致命地诱变HIV基因组，减弱病毒感染性。我们的研究结果揭示了人半乳糖凝集素-9的一种新的生物学功能，并证明了感染细胞表面的宿主聚糖介导了定义HIV转录状态和感染性的信号。我们的研究结果表明，半乳糖凝集素-9和宿主糖基化机制可能被利用，以消除潜伏的HIV水库。
Identifying host immune determinants governing HIV transcription, latency and infectivity in vivo is critical to developing an HIV cure. Based on our recent finding that the host factor p21 regulates HIV transcription during antiretroviral therapy (ART), and published data demonstrating that the human carbohydrate-binding immunomodulatory protein galectin-9 regulates p21, we hypothesized that galectin-9 modulates HIV transcription. We report that the administration of a recombinant, stable form of galectin-9 (rGal-9) potently reverses HIV latency in vitro in the J-Lat HIV latency model. Furthermore, rGal-9 reverses HIV latency ex vivo in primary CD4+ T cells from HIV-infected, ART-suppressed individuals (p = 0.002), more potently than vorinostat (p = 0.02). rGal-9 co-administration with the latency reversal agent "JQ1", a bromodomain inhibitor, exhibits synergistic activity (p<0.05). rGal-9 signals through N-linked oligosaccharides and O-linked hexasaccharides on the T cell surface, modulating the gene expression levels of key transcription initiation, promoter proximal-pausing, and chromatin remodeling factors that regulate HIV latency. Beyond latent viral reactivation, rGal-9 induces robust expression of the host antiviral deaminase APOBEC3G in vitro and ex vivo (FDR<0.006) and significantly reduces infectivity of progeny virus, decreasing the probability that the HIV reservoir will be replenished when latency is reversed therapeutically. Lastly, endogenous levels of soluble galectin-9 in the plasma of 72 HIV-infected ART-suppressed individuals were associated with levels of HIV RNA in CD4+ T cells (p<0.02) and with the quantity and binding avidity of circulating anti-HIV antibodies (p<0.009), suggesting a role of galectin-9 in regulating HIV transcription and viral production in vivo during therapy. Our data suggest that galectin-9 and the host glycosylation machinery should be explored as foundations for novel HIV cure strategies. While antiretroviral therapy (ART) has significantly decreased the morbidity and mortality associated with HIV infection, a cure is not achieved due to the persistence of HIV latently-infected cells during treatment. Identifying the principal host immune determinants governing HIV transcription, latency, and infectivity in vivo will be a critical step in developing an effective curative strategy for HIV infection. In this study, we demonstrate that the human immunomodulatory carbohydrate-binding protein galectin-9 is a determinant of HIV latency in HIV-infected individuals on suppressive ART. Administration of galectin-9 potently reactivates latent HIV in CD4+ T cells ex vivo, by signaling through specific glycans on the cell surface to modulate the gene expression levels of key host factors that regulate HIV transcription. Furthermore, galectin-9 induces the host APOBEC3 proteins which lethally mutagenize the HIV genome, attenuating viral infectivity. Our findings reveal a novel biological function of human galectin-9, and demonstrate that host glycans on the surface of infected cells mediate signals that define the transcriptional state and infectivity of HIV. Our findings suggest that galectin-9 and the host glycosylation machinery may be exploited to eradicate the latent HIV reservoir.