# SMAC mimetics sensitize HIV-infected cells to oncolytic virus-mediated death

## TL;DR

This study shows that combining SMAC mimetics with oncolytic viruses can help kill HIV-infected cells that are otherwise resistant to treatment.

## Contribution

The novel finding is that SMAC mimetics enhance oncolytic virus-induced death of HIV-infected cells through multiple mechanisms.

## Key findings

- SMAC mimetics increase MG1-mediated death of HIV-infected cells.
- The cell death involves both caspase-dependent and caspase-independent pathways.
- The effect is not due to increased virus infection but rather enhanced cell death.

## Abstract

Elimination of latently and persistently HIV-infected cells is one of the main barriers to finding a cure for HIV. We have demonstrated that cells latently/persistently infected with HIV impair interferon signaling, which makes them susceptible to selective infection and killing by the oncolytic virus (OV) MG1. Sensitizing these cells to MG1-mediated killing can be expected to make MG1 a more effective therapeutic. As small-molecule second mitochondria-derived activator of caspases (SMAC) mimetics have been shown to increase OV-mediated death in cancer models, we used the SMAC mimetics LCL-161 and birinapant alongside MG1 to enhance the killing of HIV-infected cell lines and monocyte-derived macrophages (MDMs). We show that SMAC mimetics enhance MG1-mediated death, but that this is not a result of an increase in OV infection. This cell death occurs via both caspase-dependent and caspase-independent mechanisms and is not completely dependent on tumor necrosis factor alpha (TNFα). Together, these results show that the use of SMAC mimetics alongside OVs may be a viable strategy to eradicate latently/persistently HIV-infected cells.