Unequal distribution of genetically-intact HIV-1 proviruses in cells expressing the immune checkpoint markers PD-1 and/or CTLA-4.
Unequal distribution of genetically-intact HIV-1 proviruses in cells expressing the immune checkpoint markers PD-1 and/or CTLA-4.
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DOI：
10.3389/fimmu.2023.1064346
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发表时间：
2023
影响因子：
7.3
通讯作者：
Palmer S
中科院分区：
文献类型：
--
作者：
Fisher K;Schlub TE;Boyer Z;Rasmussen TA;Rhodes A;Hoh R;Hecht FM;Deeks SG;Lewin SR;Palmer S
尽管采用了抗逆转录病毒疗法（ART），HIV - 1仍在静止的CD4 + T细胞中持续存在。确定能富集基因完整的HIV - 1基因组的细胞表面标志物，对于制定有针对性的治愈策略至关重要。先前的研究发现，HIV - 1前病毒DNA在表达免疫检查点标志物程序性细胞死亡蛋白 - 1（PD - 1）或细胞毒性T淋巴细胞相关蛋白 - 4（CTLA - 4）的CD4 + T细胞中富集。在阻断这些标志物以逆转HIV - 1潜伏状态方面也取得了一些成果。然而，表达PD - 1和/或CTLA - 4的细胞是否富集基因完整且具有潜在复制能力的HIV - 1基因组，目前仍不清楚。
我们在有效ART治疗期间，从16名HIV - 1感染参与者身上获取了外周血，并从其中4名参与者身上获取了配对的淋巴结样本。将来自任一部位的记忆CD4 + T细胞分为四个群体：PD - 1 - CTLA - 4 - （双阴性，DN）、PD - 1 + CTLA - 4 - （PD - 1 + ）、PD - 1 - CTLA - 4 + （CTLA - 4 + ）和PD - 1 + CTLA - 4 + （双阳性，DP）。我们使用全长单个前病毒测序（FLIPS）检测法进行了一项探索性研究，以识别每个亚群中基因完整和有缺陷的基因组，以及具有特定完整开放阅读框（ORF）的HIV - 1基因组。
在外周血中，我们观察到与DN、CTLA - 4 + 和DP细胞相比，PD - 1 + 细胞内的前病毒更有可能具有完整的tat、rev和nef等基因的开放阅读框，所有这些都可能导致HIV - 1持续存在。相反，我们观察到CTLA - 4的表达是携带HIV - 1前病毒且更有可能存在缺陷的细胞的标志物，这些细胞中这些完整开放阅读框的水平较低。在淋巴结中，我们发现有证据表明，与其他细胞亚群相比，CTLA - 4 + 细胞中HIV - 1前病毒的水平较低。然而，重要的是，我们观察到在这些记忆CD4 + T细胞亚群中，基因完整的HIV - 1前病毒或具有特定完整开放阅读框的前病毒的富集情况在参与者之间存在显著差异，因此可能需要考虑其他细胞标志物，以便始终如一地识别携带潜伏且具有潜在复制能力的HIV - 1的细胞。
HIV-1 persists in resting CD4+ T-cells despite antiretroviral therapy (ART). Determining the cell surface markers that enrich for genetically-intact HIV-1 genomes is vital in developing targeted curative strategies. Previous studies have found that HIV-1 proviral DNA is enriched in CD4+ T-cells expressing the immune checkpoint markers programmed cell death protein-1 (PD-1) or cytotoxic T-lymphocyte associated protein-4 (CTLA-4). There has also been some success in blocking these markers in an effort to reverse HIV-1 latency. However, it remains unclear whether cells expressing PD-1 and/or CTLA-4 are enriched for genetically-intact, and potentially replication-competent, HIV-1 genomes. We obtained peripheral blood from 16 HIV-1-infected participants, and paired lymph node from four of these participants, during effective ART. Memory CD4+ T-cells from either site were sorted into four populations: PD-1-CTLA-4- (double negative, DN), PD-1+CTLA-4- (PD-1+), PD-1-CTLA-4+ (CTLA-4+) and PD-1+CTLA-4+ (double positive, DP). We performed an exploratory study using the full-length individual proviral sequencing (FLIPS) assay to identify genetically-intact and defective genomes from each subset, as well as HIV-1 genomes with specific intact open reading frames (ORFs). In peripheral blood, we observed that proviruses found within PD-1+ cells are more likely to have intact ORFs for genes such as tat, rev and nef compared to DN, CTLA-4+ and DP cells, all of which may contribute to HIV-1 persistence. Conversely, we observed that CTLA-4 expression is a marker for cells harbouring HIV-1 provirus that is more likely to be defective, containing low levels of these intact ORFs. In the lymph node, we found evidence that CTLA-4+ cells contain lower levels of HIV-1 provirus compared to the other cell subsets. Importantly, however, we observed significant participant variation in the enrichment of HIV-1 proviruses with intact genomes or specific intact ORFs across these memory CD4+ T-cell subsets, and therefore consideration of additional cellular markers will likely be needed to consistently identify cells harbouring latent, and potentially replication-competent, HIV-1.
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影响因子：
5.4
作者：
Wang, Xiao Qian;Zerbato, Jennifer M.;Avihingsanon, Anchalee;Fisher, Katie;Schlub, Timothy;Rhodes, Ajantha;Audsley, Jennifer;Singh, Kasha P.;Zhao, Wei;Lewin, Sharon R.;Palmer, Sarah
通讯作者：
Palmer, Sarah
影响因子：
6.7
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
通讯作者：
Chomont N
DOI：
10.1073/pnas.94.24.13193
发表时间：
1997-11-25
影响因子：
11.1
作者：
Chun, TW;Stuyver, L;Fauci, AS
通讯作者：
Fauci, AS
影响因子：
7.3
作者：
Banga, Riddhima;Procopio, Francesco A.;Perreau, Matthieu
通讯作者：
Perreau, Matthieu
影响因子：
6.7
作者：
Collins DR;Collins KL
通讯作者：
Collins KL