CD4+ T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART.
CD4+ T Cells Expressing PD-1, TIGIT and LAG-3 Contribute to HIV Persistence during ART.
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DOI：
10.1371/journal.ppat.1005761
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发表时间：
2016-07
期刊：
影响因子：
6.7
通讯作者：
Chomont N
中科院分区：
文献类型：
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作者：
Fromentin R;Bakeman W;Lawani MB;Khoury G;Hartogensis W;DaFonseca S;Killian M;Epling L;Hoh R;Sinclair E;Hecht FM;Bacchetti P;Deeks SG;Lewin SR;Sékaly RP;Chomont N
尽管接受了抗逆转录病毒疗法(ART)，艾滋病毒仍持续存在于一小群潜伏感染的细胞中。识别这些细胞表面表达的细胞标志物可能会导致新的治疗策略，以减少艾滋病毒储存库的大小。我们假设，在接受抑制性抗逆转录病毒治疗的患者中，表达免疫检查点分子的CD4+T细胞会在HIV感染细胞中得到丰富。检测了48例病毒抑制者PBMC中7种免疫检查点分子(PD-1、CTLA-4、LAG-3、TIGIT、TIM-3、CD160和2B4)以及4种HIV持久性标志物(完整和总HIV DNA、2-LTR环和细胞相关非剪接HIV RNA)的表达水平。使用负二项回归模型，我们确定PD-1、TIGIT和LAG-3是免疫检查点分子，与携带整合HIV DNA的CD4+T细胞的频率呈正相关。共表达PD-1、TIGIT和LAG-3的CD4+T细胞的频率独立地预测了携带整合HIV DNA的细胞的频率。对血液中高纯度细胞亚群中HIV基因组的定量进一步表明，PD-1、TIGIT和LAG-3的表达与不同记忆CD4+T细胞亚群中的HIV感染细胞有关。同时表达这三个标记的CD4+T细胞高度浓缩了整合的病毒基因组(中位数为总CD4+T细胞的8.2倍)。重要的是，大多数携带可诱导HIV基因组的细胞至少表达其中一个标记(表达LAG-3、PD-1或TIGIT的细胞对可诱导库的贡献中位数=76%)。我们的数据提供了证据，表明在抗逆转录病毒治疗期间，单独或联合表达PD-1、TIGIT和LAG-3的CD4+T细胞对持续HIV具有丰富的作用，并表明针对这些受体的免疫检查点阻滞剂可能是针对病毒抑制个体中潜伏感染细胞的有价值的工具。艾滋病毒在一小群长期潜伏感染的静止的CD4+T细胞中的持久性是根除病毒的主要障碍。识别在潜伏感染细胞表面优先表达的细胞标志物可能会导致治愈HIV感染的新的治疗策略。我们发现PD-1、TIGIT和LAG-3是接受抗逆转录病毒治疗的个体感染细胞表面优先表达的标志物。共表达这些标记的CD4+T细胞对携带HIV的细胞高度浓缩。我们的结果表明，PD-1、TIGIT和LAG-3可能是在抗逆转录病毒治疗期间干扰HIV持续存在的新的分子靶点。
HIV persists in a small pool of latently infected cells despite antiretroviral therapy (ART). Identifying cellular markers expressed at the surface of these cells may lead to novel therapeutic strategies to reduce the size of the HIV reservoir. We hypothesized that CD4+ T cells expressing immune checkpoint molecules would be enriched in HIV-infected cells in individuals receiving suppressive ART. Expression levels of 7 immune checkpoint molecules (PD-1, CTLA-4, LAG-3, TIGIT, TIM-3, CD160 and 2B4) as well as 4 markers of HIV persistence (integrated and total HIV DNA, 2-LTR circles and cell-associated unspliced HIV RNA) were measured in PBMCs from 48 virally suppressed individuals. Using negative binomial regression models, we identified PD-1, TIGIT and LAG-3 as immune checkpoint molecules positively associated with the frequency of CD4+ T cells harboring integrated HIV DNA. The frequency of CD4+ T cells co-expressing PD-1, TIGIT and LAG-3 independently predicted the frequency of cells harboring integrated HIV DNA. Quantification of HIV genomes in highly purified cell subsets from blood further revealed that expressions of PD-1, TIGIT and LAG-3 were associated with HIV-infected cells in distinct memory CD4+ T cell subsets. CD4+ T cells co-expressing the three markers were highly enriched for integrated viral genomes (median of 8.2 fold compared to total CD4+ T cells). Importantly, most cells carrying inducible HIV genomes expressed at least one of these markers (median contribution of cells expressing LAG-3, PD-1 or TIGIT to the inducible reservoir = 76%). Our data provide evidence that CD4+ T cells expressing PD-1, TIGIT and LAG-3 alone or in combination are enriched for persistent HIV during ART and suggest that immune checkpoint blockers directed against these receptors may represent valuable tools to target latently infected cells in virally suppressed individuals. The persistence of HIV in a small pool of long-lived latently infected resting CD4+ T cells is a major barrier to viral eradication. Identifying cellular markers that are preferentially expressed at the surface of latently infected cells may lead to novel therapeutic strategies to cure HIV infection. We identified PD-1, TIGIT and LAG-3 as markers preferentially expressed at the surface of infected cells in individuals receiving ART. CD4+ T cells co-expressing these markers were highly enriched for cells carrying HIV. Our results suggest that PD-1, TIGIT and LAG-3 may represent new molecular targets to interfere with HIV persistence during ART.