cIAP1/2-TRAF2-Src-MyD88 Complex Regulates Lipopolysaccharide-Induced IL-27 Production through NF-kB Activation in Human Macrophages

Volunteer donation of blood helped us to better understand the mode of action of “smac mimetics” drugs. These results were published in the Journal of Immunology in March 2018.

The immune system is adjusted and coordinated (turned on/off) by a complex interaction of genes, signals and other ways that induce cells to survive, multiply or die in response to infections or cancers. We studied a new class of drugs called “smac mimetics” that help in signals to allow infected cells to die off and may play a role in flushing out HIV hidden in CD4+ T cells. Smac mimetics block a specific gene (the IAP gene) responsible for cell survival and so lead to cell death. We have shown in lab samples that smac mimetics cause death of HIV-infected macrophages from HIV-infected naïve and ART-treated individuals, but not uninfected macrophages. It is important to understand their clinical implications. Survival and protection of “healthy” cells of course are desirable so that coordination (on/off) is optimal.

 

1) What was the goal of our study?

The goal of this study was to understand what happens when IAP genes are blocked by the use of smac mimetics with respect to the functioning of primary human cells. Macrophages, in addition to killing some infected cells, produce proteins which are responsible for cell survival, inflammation, and the regulation of immune responses to viruses, either on their own or following activation with bacterial products such as lipopolysaccharides (LPS). IL-27 is one of the proteins produced by the macrophages following activation with LPS. IL-27 has multiple functions in inflammation and immune regulation (on/off), and also serves an anti-HIV function by inhibiting HIV replication in CD4+ T cells and macrophages. We investigated the impact of smac mimetics on macrophages functions by studying IL-27 production following activation with LPS.

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2) How is this study related to a cure for HIV? Or to treat HIV comorbidities?

This study does not yet show a direct relationship with HIV cure strategies. Smac mimetics have been shown to impact HIV latency in CD4+ T cells and to selectively kill HIV-infected macrophages while preserving uninfected cells. Thus, smac mimetics may prove to be a novel HIV cure strategy by eliminating HIV-infected macrophages in addition to playing a role in the reversal of HIV latency in CD4+ cells.

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3) Why are participant samples important to this research?

Blood samples to study in the lab from healthy participants were essential for us to obtain macrophages. We determined the impact of smac mimetics on the function of these macrophages by analyzing their production of IL-27 following activation with LPS. These samples helped us to show that in addition to killing HIV-infected macrophages, smac mimetics inhibited the production of IL-27 following stimulation with LPS.

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4) What was learned? What next?

This study explained in detail how smac mimetics can discriminate in killing infected cells and not uninfected cells. Moreover, we have learned more about the signaling pathways that regulate IL-27 production in human macrophages. More research is required to understand the clinical implications of using smac mimetics in people with HIV and cancer but this advance is encouraging in our steps to use smac mimetics in HIV treatment and functional cure.