TRAIL（DR5）受体与HIV感染者中TRAIL通路的调节：HIV疾病进展的关键机制

TRAIL (DR5) receptor and the modulation of TRAIL pathway in PLWHIV: key mechanisms in the progression of HIV disease.

作者信息

Ratkovich-Gonzalez Sarah, Ruiz-Briseño Mariana Del Rocio, De Arcos-Jiménez Judith Carolina, Alvarez-Zavala Monserrat, Andrade-Villanueva Jaime Federico, Martínez-Ayala Pedro, Ruíz-Herrera Vida V, Gonzalez-Hernandez Luz Alicia, Sánchez-Reyes Karina

机构信息

Monterrey Institute of Technology and Higher Education, School of Medicine and Health Sciences, Avenida General Ramón Corona 2514 Nuevo México, Zapopan, Jalisco, 45138, Mexico.

Department of Technological and Industrial Processes, Western Institute of Technology and Higher Studies (ITESO), Anillo Perif. Sur Manuel Gómez Morín 8585, Santa María Tequepexpan, San Pedro Tlaquepaque, Jalisco, 45604, Mexico.

出版信息

BMC Mol Cell Biol. 2025 Jun 1;26(1):17. doi: 10.1186/s12860-025-00541-z.

DOI:10.1186/s12860-025-00541-z

PMID:40452022

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12128504/

Abstract

BACKGROUND

HIV infection is mainly described by depletion of CD4 T-cells; however, this not only occurs in infected cells, also arise in uninfected immunological cells through the bystander effect. Extrinsic cell death, in particular the Fas pathway has been studied in HIV extensively, and an expression increase in both its ligand and receptor has been reported, however the TRAIL pathway has been less explored in this context, and little has been relating to the immune activation characteristic of the disease. This study aims to examine the effect of HIV infection in the activation of TRAIL and Fas death pathways in CD3 CD4 T-cells and CD4 CD14 + monocyte derived from people living with HIV (PLWHIV) and its correlation with immune activation biomarkers in cell surface and serum.

RESULTS

Expression of TRAIL receptor DR5 in CD3 CD4 T-cells and CD14 CD4 monocytes from PLWHIV were significatively increased, almost two and five times more than CD3 CD4 T-cells and CD14 CD4 monocytes from HIV-negative controls; respectively. In PLWHIV, DR5 and CCR5 expression were positively and negatively associated with time of infection; respectively. Simultaneously, DR5 was associated positively with CXCR4 expression in CD3 CD4-T cells and CD4 CD14 monocytes as well as the significant increase of serum levels of IL-18 in PLWHIV. In CD3 CD4-T cells from HIV patients, the expression of CD38 was upregulated. Finally, in CD14 CD4 monocytes from PLWHIV, it was observed an increase in early apoptosis in response to recombinant TRAIL ligand, an effect that was not inhibited by caspase 8 blockade.

CONCLUSIONS

In PLWHIV before ART, the activation and regulation of TRAIL pathway shows to be an important regulator in cell depletion. The expression of TRAIL DR5 significantly increased in CD3 CD4-T cells and CD4 CD14 monocytes from PLWHIV; in the same way DR5 was positively correlated with time of infection, with CXCR4 expression and with the significant increase in serum levels of IL-18, making it an interesting target for future treatments and as a marker for HIV disease progression.

摘要

背景

HIV感染主要表现为CD4 T细胞耗竭；然而，这不仅发生在被感染的细胞中，也通过旁观者效应出现在未感染的免疫细胞中。外在细胞死亡，特别是Fas途径已在HIV研究中得到广泛研究，并且已报道其配体和受体的表达均增加，然而在这种情况下TRAIL途径的研究较少，且与该疾病的免疫激活特征相关性不大。本研究旨在探讨HIV感染对来自HIV感染者（PLWHIV）的CD3 CD4 T细胞和CD4 CD14 +单核细胞中TRAIL和Fas死亡途径激活的影响及其与细胞表面和血清中免疫激活生物标志物的相关性。

结果

PLWHIV的CD3 CD4 T细胞和CD14 CD4单核细胞中TRAIL受体DR5的表达显著增加，分别比HIV阴性对照的CD3 CD4 T细胞和CD14 CD4单核细胞高出近两倍和五倍。在PLWHIV中，DR5和CCR5的表达分别与感染时间呈正相关和负相关。同时，DR5与CD3 CD4 - T细胞和CD4 CD14单核细胞中的CXCR4表达呈正相关，并且与PLWHIV中血清IL - 18水平的显著升高相关。在HIV患者的CD3 CD4 - T细胞中，CD38的表达上调。最后，在PLWHIV的CD14 CD4单核细胞中，观察到对重组TRAIL配体的早期凋亡增加，该效应不受caspase 8阻断的抑制。

结论

在接受抗逆转录病毒治疗（ART）之前的PLWHIV中，TRAIL途径的激活和调节显示为细胞耗竭的重要调节因子。PLWHIV的CD3 CD4 - T细胞和CD4 CD14单核细胞中TRAIL DR5的表达显著增加；同样，DR5与感染时间、CXCR4表达以及血清IL - 18水平的显著升高呈正相关，使其成为未来治疗的有趣靶点以及HIV疾病进展的标志物。