Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection
Short-Course Toll-Like Receptor 9 Agonist Treatment Impacts Innate Immunity and Plasma Viremia in Individuals With Human Immunodeficiency Virus Infection
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DOI：
10.1093/cid/cix201
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发表时间：
2017-06-15
影响因子：
11.8
通讯作者：
Sogaard, Ole S.
中科院分区：
文献类型：
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作者：
Vibholm, Line;Schleimann, Mariane H.;Sogaard, Ole S.
背景潜伏期逆转剂（LRA）治疗增强人类免疫缺陷病毒1型（HIV-1）在体内的转录，但导致水库的大小只有适度的减少，可能是由于不充分的免疫介导的消除感染细胞。我们假设一个单一的药物分子-一种新型的Toll样受体9（TLR 9）激动剂，MGN 1703-可以作为先天免疫增强剂和体内LRA。我们进行了一项单臂、开放标签研究，其中15名接受抗逆转录病毒治疗的病毒学抑制HIV-1感染者接受60 mg MGN 1703皮下注射，每周两次，持续4周。我们在基线和治疗4周后使用流式细胞术表征浆细胞样树突状细胞、自然杀伤细胞（NK）和T细胞活化。通过测量MGN 1703给药期间血浆HIV-1 RNA定量HIV-1转录。根据TLR 9的细胞类型特异性表达，MGN 1703处理导致浆细胞样树突状细胞的显著活化和血浆干扰素-α 2水平的显著增加（P < .0001）。同样，干扰素刺激的基因（例如，OAS 1，ISG 15，Mx 1;每个P <0.0001）的转录在CD 4（+）T细胞中上调，如RNA测序所示。此外，活化的细胞毒性NK细胞和CD 8（+）T细胞的比例在MGN 1703给药期间显著增加，表明细胞免疫应答增强。15名参与者中有6名在治疗期间血浆HIV-1 RNA从1500拷贝/mL（范围21-1571拷贝/mL）升高。HIV感染中的TLR 9激动剂治疗具有增加HIV-1转录和增强细胞毒性NK细胞活化的双重潜力，这两者都是HIV-1根除治疗的关键结果。
Background. Treatment with latency reversing agents (LRAs) enhances human immunodeficiency virus type 1 (HIV-1) transcription in vivo but leads to only modest reductions in the size of the reservoir, possibly due to insufficient immune-mediated elimination of infected cells. We hypothesized that a single drug molecule-a novel Toll-like receptor 9 (TLR9) agonist, MGN1703-could function as an enhancer of innate immunity and an LRA in vivo.Methods. We conducted a single-arm, open-label study in which 15 virologically suppressed HIV-1-infected individuals on antiretroviral therapy received 60 mg MGN1703 subcutaneously twice weekly for 4 weeks. We characterized plasmacytoid dendritic cell, natural killer (NK), and T-cell activation using flow cytometry on baseline and after 4 weeks of treatment. HIV-1 transcription was quantified by measuring plasma HIV-1 RNA during MGN1703 administration.Results. In accordance with the cell type-specific expression of TLR9, MGN1703 treatment led to pronounced activation of plasmacytoid dendritic cells and substantial increases in plasma interferon-alpha 2 levels (P < .0001). Consistently, transcription of interferon-stimulated genes (eg, OAS1, ISG15, Mx1; each P < .0001) were upregulated in CD4(+) T cells as demonstrated by RNA sequencing. Further, proportions of activated cytotoxic NK cells and CD8(+) T cells increased significantly during MGN1703 dosing, suggesting an enhancement of cellular immune responses. In 6 of 15 participants, plasma HIV-1 RNA increased from 1500 copies/mL (range, 21-1571 copies/mL) during treatment.Conclusions. TLR9 agonist treatment in HIV infection has a dual potential by increasing HIV-1 transcription and enhancing cytotoxic NK cell activation, both of which are key outcomes in HIV-1 eradication therapy.