TNF and TNF Receptor Superfamily Members in HIV infection: New Cellular Targets for Therapy?

Amit Kumar,Georges Herbein,Wasim Abbas

doi:10.1155/2013/484378

Abstract

Tumor necrosis factor (TNF) and TNF receptors (TNFR) superfamily members are engaged in diverse cellular phenomena such as cellular proliferation, morphogenesis, apoptosis, inflammation, and immune regulation. Their role in regulating viral infections has been well documented. Viruses have evolved with numerous strategies to interfere with TNF-mediated signaling indicating the importance of TNF and TNFR superfamily in viral pathogenesis. Recent research reports suggest that TNF and TNFRs play an important role in the pathogenesis of HIV. TNFR signaling modulates HIV replication and HIV proteins interfere with TNF/TNFR pathways. Since immune activation and inflammation are the hallmark of HIV infection, the use of TNF inhibitors can have significant impact on HIV disease progression. In this review, we will describe how HIV infection is modulated by signaling mediated through members of TNF and TNFR superfamily and in turn how these latter could be targeted by HIV proteins. Finally, we will discuss the emerging therapeutics options based on modulation of TNF activity that could ultimately lead to the cure of HIV-infected patients.

Highlights

The term tumor necrosis factor (TNF) came into existence in 1975 with the work of Carswell and colleagues while studying hemorrhagic necrosis by endotoxin [1]
Tumor necrosis factor (TNF)-alpha can induce cell proliferation through induction of transcription factor called activator protein-1 (AP-1) by binding to TNFR1 followed by sequential contribution of TNFRassociated death domain (TRADD), TRAF2-receptor interacting protein (RIP), MEKK1, MKK7 and JNK [4, 7, 20] (Figure 1)
In vitro testing of recombinant TNF-related apoptosis-inducing ligand (TRAIL) against HIV-infected peripheral blood lymphocytes and monocyte-derived macrophages isolated from HIV-infected patients results in apoptosis of the target cells

Summary

Introduction

The term tumor necrosis factor (TNF) came into existence in 1975 with the work of Carswell and colleagues while studying hemorrhagic necrosis by endotoxin [1]. TNF and TNF receptors (TNFR) are growing members of ligand and receptor superfamily that regulate several complex signaling pathways leading to apoptosis, inflammation, cellular differentiation, and antiviral state. The first member of TNF superfamily discovered is TNF-alpha (old name cachectin), a pleiotropic proinflammatory cytokine that plays pivotal role in several pathological conditions due to inflammation and infection [2]. Role of TNF in malignancies and inflammation conditions like arthritis have been reviewed extensively elsewhere [3,4,5]. Presence of death domain is critical for the interaction with other proteins leading to cell death. Under certain pathophysiological conditions their presence has been documented in other cell types as well

TNF-Alpha-Mediated Cell Signaling

TNFR1 and TNFR2

Targeting Members of TNF and TNFR Superfamily in HIV-1 Infection

Conclusion