Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD, United States.
Department of Pediatric Infectious Disease, Johns Hopkins University School of Medicine, Baltimore, MD, United States.
Front Immunol. 2023 Mar 23;14:1007626. doi: 10.3389/fimmu.2023.1007626. eCollection 2023.
HIV-1 infection in memory CD4+ T cells forms a latent reservoir that is a barrier to cure. Identification of immune biomarkers that correlate with HIV-1 reservoir size may aid with evaluating efficacy of HIV-1 eradication strategies, towards ART-free remission and cure. In adults living with non-perinatal HIV-1, the immune exhaustion marker PD-1 on central memory CD4+ T cells (Tcm) correlates with measures of HIV-1 reservoir size. Immune correlates of HIV-1 are less defined in adolescents and young adults with perinatal HIV-1. With multi-parameter flow cytometry, we examined immune activation (CD69, CD25, HLA-DR), and exhaustion (PD-1, TIGIT, TIM-3 and LAG-3) markers on CD4+ T cell subsets (naïve (Tn), central memory (Tcm), and the combination (Ttem) of transitional (Ttm) and effector memory (Tem) cells, in 10 adolescents and young adults living with perinatal HIV-1 (median age 15.9 years; median duration of virologic suppression 7.0 years), in whom HIV-1 reservoir size was measured with the Intact Proviral HIV-1 DNA Assay (IPDA) and an enhanced Tat/Rev limiting dilution assay (TILDA). RNA-seq was also performed on the unstimulated CD4+ T cells. The median total HIV-1 DNA concentration in memory CD4+ T cells was 211.90 copies per million CD4+ T cells. In the 7 participants with subtype B HIV-1 infection, the median intact proviral DNA load was 7.96 copies per million CD4+ T cells. Levels of HLA-DR and TIGIT on the Ttem were correlated with total HIV-1 DNA (r=0.76, p=0.015) and (r=0.72, p=0.023), respectively, but not with intact proviral load or induced reservoir size. HIV-1 DNA load was also positively correlated with transcriptional clusters associated with HLA-DR expression by RNA-seq. In contrast, PD-1 expression on Tcm was inversely correlated with total HIV-1 DNA (r=-0.67, p=0.039). Reservoir size by IPDA and TILDA were correlated (r=0.81, p=0.036). Thus, in this cohort of youths with long-standing treated perinatal infection, HLA-DR and TIGIT on Ttem were the key correlates of HIV-1 infected cell frequencies by total HIV-1 DNA, and not PD-1. Total HIV-1 DNA was negatively correlated with PD-1 expressing Tcm. These differences in longstanding perinatal HIV-1 infection compared with adult infection requires further study in larger cohorts.
HIV-1 感染记忆 CD4+T 细胞形成潜伏储库，这是治愈的障碍。鉴定与 HIV-1 储库大小相关的免疫生物标志物可能有助于评估 HIV-1 清除策略的疗效，实现无 ART 缓解和治愈。在非围生期 HIV-1 感染的成年人中，中央记忆 CD4+T 细胞（Tcm）上的免疫衰竭标志物 PD-1 与 HIV-1 储库大小的测量值相关。在围生期 HIV-1 感染的青少年和年轻人中，HIV-1 的免疫相关性定义较少。我们使用多参数流式细胞术，检查了 10 名围生期 HIV-1 感染的青少年和年轻人（中位年龄 15.9 岁；中位病毒抑制时间 7.0 年）的 CD4+T 细胞亚群（幼稚（Tn）、中央记忆（Tcm）和过渡（Ttm）和效应记忆（Tem）细胞的组合（Ttem）上的免疫激活（CD69、CD25、HLA-DR）和衰竭（PD-1、TIGIT、TIM-3 和 LAG-3）标志物，通过完整原病毒 HIV-1 DNA 检测（IPDA）和增强的 Tat/Rev 限量稀释检测（TILDA）测量 HIV-1 储库大小。未刺激的 CD4+T 细胞也进行了 RNA-seq 分析。记忆 CD4+T 细胞中总 HIV-1 DNA 浓度的中位数为 211.90 拷贝/百万 CD4+T 细胞。在 7 名感染 B 亚型 HIV-1 的参与者中，完整原病毒 DNA 载量的中位数为 7.96 拷贝/百万 CD4+T 细胞。Ttem 上的 HLA-DR 和 TIGIT 水平与总 HIV-1 DNA（r=0.76，p=0.015）和（r=0.72，p=0.023）呈正相关，但与完整原病毒载量或诱导的储库大小无关。HIV-1 DNA 载量也与 RNA-seq 中 HLA-DR 表达相关的转录簇呈正相关。相比之下，Tcm 上的 PD-1 表达与总 HIV-1 DNA 呈负相关（r=-0.67，p=0.039）。IPDA 和 TILDA 测定的储库大小相关（r=0.81，p=0.036）。因此，在这个长期接受治疗的围生期感染的年轻人队列中，Ttem 上的 HLA-DR 和 TIGIT 是总 HIV-1 DNA 感染细胞频率的关键相关因素，而不是 PD-1。总 HIV-1 DNA 与表达 PD-1 的 Tcm 呈负相关。与成人感染相比，长期围生期 HIV-1 感染存在这些差异，需要在更大的队列中进一步研究。
