Toll-like Receptor 7 Agonists in People Living With HIV: Implications for Immunotherapeutic Strategies for an HIV Cure.
Toll-like Receptor 7 Agonists in People Living With HIV: Implications for Immunotherapeutic Strategies for an HIV Cure.
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HIV 感染者中的 Toll 样受体 7 激动剂：对 HIV 治愈免疫治疗策略的影响。
DOI：
10.1093/cid/ciaa1539
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
Lewin,SharonR
中科院分区：
文献类型：
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作者：
Rasmussen,ThomasA;Lewin,SharonR
联合抗逆转录病毒疗法（ART）可以有效地将艾滋病毒抑制到非常低或无法检测到的水平，但需要终生治疗。这是因为 HIV 可以整合到长寿且增殖的 CD4+ T 细胞的 DNA 中，并且不会完成病毒生命周期，而是以沉默形式持续存在，病毒转录很少或没有。因此，这些细胞不会被 HIV 特异性 T 细胞清除，也不会对抗逆转录病毒药物产生反应 [1]。为了在 ART 之外实现治愈或控制病毒复制，人们对能够减少受感染细胞池和增强免疫控制的干预措施非常感兴趣。激活潜伏感染细胞中的 HIV 转录和蛋白质表达以实现免疫识别是减少感染细胞池的一种方法。这通常被称为潜伏期逆转或“休克和杀死”[2]。针对 TLR-7 或 TLR-9 的 Toll 样受体 (TLR) 激动剂作为潜在的治疗策略受到高度关注，因为它们能够逆转 HIV 潜伏期并增强 HIV 特异性免疫控制 [3, 4]。在本期《临床传染病》中，Riddler 等人报告了 TLR-7 激动剂 vesatolimod 在艾滋病患者中的首次临床试验。 HIV (PLWH) [ref Riddler 等人，CID 2020] 由资助该试验的吉利德科学公司开发，作者以 6:2 的比例随机接受 10 剂 vesatolimod，每 2 周一次，剂量范围为 1-12 mg，或匹配的安慰剂。次要终点和探索性终点均与维沙托莫德是否对逆转 HIV 潜伏期或耗尽病毒库有任何影响有关，不幸的是，维沙托莫德对任何病毒学参数没有影响，但通过干扰素刺激基因 (ISG)（如干扰素 y 诱导蛋白 10 (IP-10)、白细胞介素 (IL)-1 和白细胞介素 (IL)-1）的 mRNA 定量来确定，存在显着的先天免疫变化。干扰素诱导性 T 细胞 α 趋化剂 (ITAC) 主要存在于浆细胞样树突状细胞 (pDC) 和 B 细胞的内体区室中 [5]，在 TLR-7 刺激下，pDC 会分泌大量 I 型干扰素 (IFN)，通过 ISG 促进细胞自主抗病毒防御，从而增强抗体依赖性免疫。免疫力和
Combination antiretroviral therapy (ART) can potently suppress HIV to very low or undetectable levels but treatment is required life long. This is because HIV can integrate in the DNA of long-lived and proliferating CD4+ T cells and, rather than complete the virus life cycle, persists in a silent form with minimal or no viral transcription. As a result, these cells are not cleared by HIV-specific T-cells and are not responsive to antiretroviral drugs [1]. To achieve a cure or control of virus replication off ART, there is significant interest in interventions capable of both reducing the pool of infected cells and enhancing immune control. Activating HIV transcription and protein expression in latently infected cells to allow for immune recognition is one approach to reduce the pool of infected cells. This is often referred to as latency reversal or “shock and kill’’[2]. Toll-like receptor (TLR) agonists targeting TLR-7 or TLR-9 are of high interest as potential cure strategies because of their capacity to both reverse HIV latency and enhance HIV-specific immune control [3, 4].In this edition of Clinical Infectious Diseases, Riddler et al. report on the first clinical trial of the TLR-7 agonist vesatolimod in people living with HIV (PLWH)[ref Riddler et al., CID 2020]. Vesatolimod was developed by Gilead Sciences who funded the trial. The authors enrolled 48 PLWH on ART and randomized 6: 2 to receive 10 doses of vesatolimod ranging from 1–12 mg once every 2 weeks, or matching placebo. The intervention was generally well tolerated with only mild and transient adverse events. Except for pharmacokinetics, the primary, secondary, and exploratory endpoints were all related to whether vesatolimod had any effect on reversing HIV latency or depleting the reservoir. Unfortunately, vesatolimod had no effect on any virological parameters, but there were significant innate immune changes, as determined by quantification of mRNA for interferon-stimulated genes (ISGs) such as interferon-y inducible protein-10 (IP-10), interleukin (IL)-1, and interferon-inducible T-cell alpha chemoattractant (ITAC). TLR-7 is predominantly found in the endosomal compartment of plasmacytoid dendritic cells (pDCs) and B cells [5]. Upon TLR-7 stimulation, pDCs secrete copious amounts of type I interferons (IFNs) that promote cell-autonomous antiviral defense through ISGs. Type I IFNs also serve as a bridge between innate and adaptive immunity, enhancing antibody-dependent immunity and