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. 1. 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]. It was described as a host factor, a glycoprotein induced in response to endotoxin that has the capacity to kill the tumor. As the time progressed, TNF was realized to be rather a member of a superfamily that governs by binding to their receptors. 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 [3–5]. Till date TNF superfamily comprises of 19 ligands and 29 receptors [4]. All members are proinflammatory in nature playing diverse roles [4]. Most of the members act like dual edge sword, both beneficial and in adverse role [4, 6, 7]. First two members of TNF ligand (TNFL) superfamily were TNF-alpha and TNF-beta, recognized first at protein level followed by identification of their respective cDNAs, while rest of the members were discovered based on cDNA sequence
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