Programmed cell death-1 contributes to the establishment and maintenance of HIV-1 latency.
Programmed cell death-1 contributes to the establishment and maintenance of HIV-1 latency.
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DOI：
10.1097/qad.0000000000001849
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发表时间：
2018-07-17
期刊：
影响因子：
--
通讯作者：
Lewin SR
中科院分区：
文献类型：
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作者：
Evans VA;van der Sluis RM;Solomon A;Dantanarayana A;McNeil C;Garsia R;Palmer S;Fromentin R;Chomont N;Sékaly RP;Cameron PU;Lewin SR
在接受抗逆转录病毒治疗(ART)的HIV感染者中，潜伏的HIV富含表达免疫检查点分子(IC)的CD4+T细胞，特别是程序性细胞死亡-1(PD-1)。因此，我们在体外和体内评估了阻断PD-1对潜伏期的影响。静息的CD4+T细胞与髓系树突状细胞共培养后，在体外建立了HIV潜伏期。流式细胞仪检测PD-1的表达，并对分选的高PD-1H和PD-1Low/−非增殖性CD+记忆性T细胞的潜伏期进行评估。通过在感染前后的共培养细胞中加入抗PD-1抗体(Pembrolizumab)来确定PD-1在建立潜伏期中的作用。此外，对接受抗逆转录病毒治疗的转移性黑色素瘤患者单次注射抗PD-1(Nivolumab)，并对细胞相关(CA)HIVDNA和RNA以及血浆HIVRNA进行了定量。与PD-1low/−非增殖、CD+记忆性T细胞相比，PD-1High组的HIV潜伏期显著增加。筛选额外的IC，T细胞免疫球蛋白结构域和粘蛋白结构域-3(TIM-3)，与PD-1结合进一步丰富潜伏期。在体外，在HIV感染前阻断PD-1导致所有捐赠者的潜伏感染细胞略有但显著减少(n=6)。抗逆转录病毒治疗后，HIV感染者体内的CA HIV RNA显著增加，而HIV DNA或血浆HIV RNA无明显变化，这与HIV潜伏期的逆转一致。PD-1有助于建立和维持艾滋病毒潜伏期，应与其他IC一起探索作为扭转潜伏期的目标。
In HIV-infected individuals on antiretroviral therapy (ART), latent HIV is enriched in CD4+ T-cells expressing immune checkpoint molecules (ICs), in particular programmed cell death-1 (PD-1). We therefore assessed the effect of blocking PD-1 on latency, both in vitro and in vivo. HIV latency was established in vitro following co-culture of resting CD4+ T-cells with myeloid dendritic cells. Expression of PD-1 was quantified by flow cytometry, and latency assessed in sorted PD-1high and PD-1low/− non-proliferating CD4+ memory T-cells. The role of PD-1 in the establishment of latency was determined by adding anti-PD-1 (pembrolizumab) to co-cultures before and after infection. Additionally, a single infusion of anti-PD-1 (nivolumab) was administered to an HIV-infected individual on ART with metastatic melanoma, and cell-associated (CA) HIV DNA and RNA, and plasma HIV RNA were quantified. HIV latency was significantly enriched in PD-1high compared to PD-1low/− nonproliferating, CD4+ memory T-cells. Sorting for an additional IC, T-cell immunoglobulin domain and mucin domain-3 (Tim-3), in combination with PD-1 further enriched for latency. Blocking PD-1 prior to HIV infection, in vitro, resulted in a modest but significant decrease in latently infected cells in all donors (n=6). The administration of anti-PD-1 to an HIV-infected individual on ART, resulted in a significant increase in CA HIV RNA in CD4+ T-cells, without significant changes in HIV DNA or plasma HIV RNA, consistent with reversal of HIV latency. PD-1 contributes to the establishment and maintenance of HIV latency and should be explored as a target, in combination with other ICs, to reverse latency.