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

## TL;DR

This study explores how the TRAIL pathway contributes to immune cell depletion in people living with HIV, highlighting its potential as a treatment target.

## Contribution

The study identifies increased TRAIL receptor DR5 expression and its correlation with immune activation markers in HIV patients.

## Key findings

- TRAIL receptor DR5 expression is significantly higher in CD3+ CD4+ T-cells and CD4+ CD14+ monocytes from PLWHIV.
- DR5 expression correlates with time of infection and serum IL-18 levels in HIV patients.
- TRAIL-induced apoptosis in CD14+ CD4+ monocytes is not inhibited by caspase 8 blockade in PLWHIV.

## Abstract

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.

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.

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.