Memory CD4+T-Cells Expressing HLA-DR Contribute to HIV Persistence During Prolonged Antiretroviral Therapy
Memory CD4+T-Cells Expressing HLA-DR Contribute to HIV Persistence During Prolonged Antiretroviral Therapy
复制标题
表达HLA-DR的记忆性CD4+ t细胞有助于延长抗逆转录病毒治疗期间HIV的持久性
DOI：
10.3389/fmicb.2019.02214
复制
发表时间：
2019-09-26
影响因子：
5.2
通讯作者：
Palmer, Sarah
中科院分区：
文献类型：
--
作者：
Lee, Eunok;Bacchetti, Peter;Palmer, Sarah
迄今为止，用于测量人类免疫缺陷病毒（HIV-1）储库的大多数测定不包括表达活化标志物人类白细胞抗原-抗原D相关（HLA-DR）的记忆性CD 4 + T细胞。然而，关于这些细胞在有效的抗逆转录病毒治疗（ART）期间维持HIV-1持续存在的作用知之甚少。为了解决这个问题，我们纵向检查了来自6名参与者的外周血的HLA-DR-和HLA-DR+记忆CD 4 + T细胞亚群中的细胞活化/耗竭标志物（Ki 67、CCR 5、PD-1、Lag-3和Tim-3）和病毒gag-pol DNA序列，这些参与者接受了3年至>= 15年的有效治疗。HLA-DR表达在研究期间在所有参与者中很容易检测到。CCR 5、PD-1和Tim-3的平均表达水平在HLA-DR+ T细胞亚群上更高，而LAG-3的平均表达在它们的HLA-DR-对应物上更高。HIV感染细胞在HLA-DR+亚群中的比例平均每年ART增加18%，而感染HLA-DR-T细胞的频率随着时间的推移略有下降（每年5%）。我们观察到早期时间点的20-33%的HIV-DNA序列与ART期间同一细胞亚群中最后一个时间点的病毒序列在遗传上相同。这表明在长期ART期间，一部分前病毒持续存在于HLA-DR+和HLA-DR-T细胞亚群中。我们的HIV-DNA序列分析还显示，细胞在HLA-DR+和HLA-DR-表型之间转换。Ki 67表达，细胞增殖的标志物，和Ki 67/PD-1的组合标志物在HLA-DR+ T细胞亚群上平均比它们的HLA-DR-对应物高19倍和22倍。此外，在研究期间，两个T细胞亚群中的细胞增殖（由遗传上相同的HIV-DNA序列的比例反映）增加;然而，这种增加在HLA-DR+ T细胞中更大。我们的研究表明，在长期治疗期间，细胞转化和增殖有助于HIV在HLA-DR+和HLA-DR-T细胞亚群中的持续存在。因此，当包括HLA-DR+和HLA-DR-细胞亚群时，HIV储库在有效的ART期间扩大，并且旨在减少HIV-1储库的治疗干预应该靶向HLA-DR+和HLA-DR-T细胞。
To date, most assays for measuring the human immunodeficiency virus (HIV-1) reservoir do not include memory CD4+ T-cells expressing the activation marker, human leukocyte antigen-antigen D related (HLA-DR). However, little is known concerning the role these cells play in maintaining persistent HIV-1 during effective antiretroviral therapy (ART). To address this issue, we examined, cellular activation/exhaustion markers (Ki67, CCR5, PD-1, Lag-3 and Tim-3) and viral gag-pol DNA sequences within HLA-DR- and HLA-DR+ memory CD4+ T-cell subsets longitudinally from the peripheral blood of six participants over 3 to >= 15 years of effective therapy. HLA-DR expression was readily detected during the study period in all participants. The average expression levels of CCR5, PD-1 and Tim-3 were higher on the HLA-DR+ T-cell subset whereas the average of LAG-3 expression was higher on their HLA-DR- counterpart. The proportion of HIV-infected cells increased within the HLA-DR+ subset by an average of 18% per year of ART whereas the frequency of infected HLA-DR- T-cells slightly decreased over time (5% per year). We observed that 20-33% of HIV-DNA sequences from the early time points were genetically identical to viral sequences from the last time point within the same cell subset during ART. This indicates that a fraction of proviruses persists within HLA-DR+ and HLA-DR- T-cell subsets during prolonged ART. Our HIV-DNA sequence analyses also revealed that cells transitioned between the HLA-DR+ and HLA-DR- phenotypes. The Ki67 expression, a marker for cellular proliferation, and the combined markers of Ki67/PD-1 averaged 19-fold and 22-fold higher on the HLA-DR+ T-cell subset compared to their HLA-DR- counterpart. Moreover, cellular proliferation, as reflected by the proportion of genetically identical HIV-DNA sequences, increased within both T-cell subsets over the study period; however, this increase was greater within the HLA-DR+ T-cells. Our research revealed that cellular transition and proliferation contribute to the persistence of HIV in HLA-DR+ and HLA-DR- T-cell subsets during prolonged therapy. As such, the HIV reservoir expands during effective ART when both the HLA-DR+ and HLA-DR- cell subsets are included, and therapeutic interventions aimed at reducing the HIV-1 reservoir should target HLA-DR+ and HLA-DR- T-cells.