Journal Article

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

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

2025

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Adult / Antibodies / Antiretroviral therapy / Apoptosis / Biological Microscopy / Biomarkers / Biomedical and Life Sciences / Care and treatment / Caspase-8 / CD14 antigen / CD3 antigen / CD38 antigen / CD4 antigen / CD4-Positive T-Lymphocytes - immunology / CD4-Positive T-Lymphocytes - metabolism / Cell activation / Cell Biology / Cell death / Cell surface / Cholesterol / Cloning / CXCR4 protein / Cytokines / Disease Progression / DR5 / Fas / FasL / Female / Health aspects / HIV / HIV infection / HIV Infections - immunology / HIV Infections - metabolism / HIV Infections - pathology / Human immunodeficiency virus / Humans / IL-18 / Infections / Inflammation / Interleukin 18 / Life Sciences / Ligands / Lipoproteins / Lymphocytes T / Macrophages / Male / Middle Aged / Monocytes / Monocytes - immunology / Monocytes - metabolism / Prevention / Receptors, CCR5 - metabolism / Receptors, CXCR4 - metabolism / Receptors, TNF-Related Apoptosis-Inducing Ligand - metabolism / Risk factors / Serum levels / Signal Transduction / TNF-Related Apoptosis-Inducing Ligand - metabolism / TRAIL / TRAIL protein / Tumor necrosis factor-TNF / Viral infections