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HIV Productively Infects Highly Differentiated and Exhausted CD4+ T Cells During AIDS

Pathogens and Immunity(2024)

INSERM UMR_S1109 | Le Trait d'Union | Clinical Virology Laboratory | Infectious Diseases Department

Cited 0|Views17
Abstract
Background: Throughout HIV infection, productively infected cells generate billions of viral particles and are thus responsible for body-wide HIV dissemination, but their phenotype during AIDS is unknown. As AIDS is associated with immunological changes, analyzing the phenotype of productively infected cells can help understand HIV production during this terminal stage. Methods: Blood samples from 15 untreated viremic participants (recent infection, n=5; long-term infection, n=5; active opportunistic AIDS-defining disease, n=5) and 5 participants virologically controlled on antiretroviral therapy (ART) enrolled in the Analysis of the Persistence, Reservoir and HIV Latency (APRIL) study (NCT05752318) were analyzed. Cells expressing the capsid protein p24 (p24+ cells) after 18 hours of resting or 24 hours of stimulation (HIV-Flow) revealed productively infected cells from viremic participants or translation-competent reservoir cells from treated participants, respectively. Results: The frequency of productively infected cells tended to be higher during AIDS in comparison with recent and long-term infections (median, 340, 72, and 32/million CD4+ T cells, respectively) and correlated with the plasma viral load at all stages of infection. Altogether, these cells were more frequently CD4low, HLA-ABClow, CD45RA-, Ki67+, PD-1+, with a non-negligible contribution from pTfh (CXCR5+PD-1+) cells, and were not significantly enriched in HIV coreceptors CCR5 nor CXCR4 expression. The comparison markers expression between stages showed that productively infected cells during AIDS were enriched in memory and exhausted cells. In contrast, the frequencies of infected pTfh were lower during AIDS compared to non-AIDS stages. A UMAP analysis revealed that total CD4+ T cells were grouped in 7 clusters and that productive p24+ cells were skewed to given clusters throughout the course of infection. Overall, the preferential targets of HIV during the latest stages seemed to be more frequently highly differentiated (memory, TTD-like) and exhausted cells and less frequently pTfh-like cells. In contrast, translation-competent reservoir cells were less frequent (5/million CD4+ T cells) and expressed more frequently HLA-ABC and less frequently PD-1. Conclusions: In long-term infection and AIDS, productively infected cells were differentiated and exhausted. This could indicate that cells with these given features are responsible for HIV production and dissemination in an immune dysfunction environment occurring during the last stages of infection.
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AIDS,recent infection,productively infected cells,phenotype,exhaustion
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要点】:本研究揭示了HIV在AIDS晚期感染高度分化的CD4+T细胞,这些细胞具有耗竭特征,并负责病毒的生产和传播。创新点在于揭示了AIDS晚期CD4+T细胞的新表型,为理解HIV在此阶段的产生和传播提供了新视角。

方法】:研究者对未治疗的病毒载量较高的参与者(近期感染5例,长期感染5例,活跃的机会性AIDS定义疾病5例)和5例抗逆转录病毒治疗(ART)病毒学控制的参与者进行了血液样本分析。通过HIV-Flow方法,用休息18小时或刺激24小时后表达包膜蛋白p24的细胞来识别病毒载量较高的参与者的产物感染细胞或治疗参与者的翻译活性储存细胞。

实验】:实验使用了来自不同感染阶段的参与者血液样本,进行了HIV-Flow分析,区分了产物感染细胞和翻译活性储存细胞。结果显示,AIDS晚期产物感染细胞频率更高,且与病毒载量相关,这些细胞更多为CD4low、HLA-ABClow、CD45RA-、Ki67+、PD-1+,pTfh(CXCR5+PD-1+)细胞贡献较大,并不显著富集HIV核心受体CCR5或CXCR4表达。与阶段相比,AIDS期间的产物感染细胞在记忆和耗竭细胞中富集,而感染pTfh在AIDS阶段较低。UMAP分析显示,总CD4+T细胞分为7个簇,产物p24+细胞在感染过程中倾向于某些簇。总体而言,HIV在感染晚期阶段更频繁地感染高度分化的(记忆、TTD-like)和耗竭细胞,而不是pTfh样细胞。相比之下,翻译活性储存细胞较少(5/百万CD4+T细胞),且更频繁地表达HLA-ABC,而较少表达PD-1。

结论:在长期感染和AIDS期间,产物感染细胞是分化和耗竭的。这可能表明具有这些特征的细胞负责HIV在感染最后阶段免疫功能障碍环境中的生产和传播。