# Evaluating the role of  the novel apoptosis inhibitor TRAILshort, in maintaining HIV persistence

> **NIH NIH R56** · MAYO CLINIC ROCHESTER · 2021 · $606,874

## Abstract

PROJECT SUMMARY
HIV infected cells escape normal host immune responses. One pathway that the immune system uses to kill
virally infected cells is TRAIL, which is expressed on activated T cells or NK cells. We have studied TRAIL
involvement in HIV infection for ~15 years and discovered that (i) despite expressing TRAIL receptors, HIV
infected cells are paradoxically resistant to the pro-death effects of TRAIL, and (ii) we discovered a splice
variant of TRAIL that is produced by HIV+ cells which we have called TRAILshort. TRAILshort binds to TRAIL
receptors and prevents normal (full length) TRAIL from killing these cells.
We therefore created fully-humanized anti-TRAILshort-specific antibodies that sequester TRAILshort, and
tested it in acute in vitro HIV infection. Anti TRAILshort antibody (or genetic inhibition of TRAILshort production)
causes more HIV infected cells to die during acute infection, resulting in reduced HIV viral replication.
We next analyzed publicly available RNAseq datasets from 253,200 human samples and identified TRAILshort
exclusively in samples from donors with active infectious diseases, and/or human malignancy. We have since
published that ~40% of human cancers express TRAILshort (by immunohistochemistry and in situ
hybridization), and that primary B cell malignancies are inefficiently killed by autologous T cells, yet in the
presence of TRAILshort antibody, that killing is significantly enhanced.
We also observed that T cells exposed to cognate antigen proliferated more in the presence of anti-TRAILshort
antibody, than in the absence, suggesting that TRAILshort might also directly impact T cell function and
proliferation. Proteomic data presented herein show that TRAILshort treatment of primary T cells results in
intracellular T signaling, changes in the cellular phosphorome, alterations in regulators of T cell activation and
function (e.g. p38, ERK, JNK and Akt). In primary T cells treated with TRAILshort protein, we observe p38
phosphorylation at residues 180/182 by western blot, and impaired T cell activation induced by T-cell receptor
(TCR) ligation (reduced CD25 and 69, less CFSE dilution and reduced Zap70 Lat phosphorylation by western
blot), altogether indicating that TRAILshort is immunosuppressive to T cells.
We will advance our understanding of the effect of TRAILshort on HIV specific T cell function by (i) testing the
effect of TRAILshort antagonism on restoring HIV-specific T cell killing of productively HIV infected cells and
latently HIV infected CD4 T cells induced to reactivate from latency, (ii) using advanced phospho-proteomic
and biochemical techniques to understand how TRAILshort binding to TRAIL receptor 2 alters T cell
homeostasis and (iii) study TCR-induced cell activation in the presence or absence of TRAILshort, to define
defects in TCR signaling, reversing the defect using genetic and small molecule approaches, as well as
TRAILshort antibodies.

## Key facts

- **NIH application ID:** 10427482
- **Project number:** 2R56AI120698-06A1
- **Recipient organization:** MAYO CLINIC ROCHESTER
- **Principal Investigator:** ANDREW D BADLEY
- **Activity code:** R56 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $606,874
- **Award type:** 2
- **Project period:** 2015-06-15 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10427482

## Citation

> US National Institutes of Health, RePORTER application 10427482, Evaluating the role of  the novel apoptosis inhibitor TRAILshort, in maintaining HIV persistence (2R56AI120698-06A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10427482. Licensed CC0.

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