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

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.

The effect of HAART-induced HIV suppression on circulating markers of inflammation and immune activation

“…Interestingly, these biomarkers include members of the TNF (TNF-α, BAFF) or the TNF-receptor (sCD27, sTNFR2) superfamilies [22], and a receptor associated with microbial translocation and stimulation by LPS (sCD14) [23]. Meanwhile, several important markers of T-cell activation (IL-2, sIL-2Ra, IFN-γ) were essentially normalized among the HIV-suppressed.…”

TNF-related weak inducer of apoptosis (TWEAK) levels in schizophrenia

“…Up to this day, 19 ligands and 29 receptors were identified in the tumor necrosis factor superfamily (Aggarwal et al, 2012;Kumar et al, 2013). Members of this superfamily have roles in many biological events including immune system development and function (Wiley and Winkles, 2003) as well as in the pathogenesis of many central nervous system diseases such as multiple sclerosis and cerebral ischemia (Feuerstein et al, 1997;Juedes et al, 2000).…”

HIV Nef- and Notch1-dependent Endocytosis of ADAM17 Induces Vesicular TNF Secretion in Chronic HIV Infection

“…As both, proTNF cleavage and TNFR shedding, require the activation of TNF-alpha converting enzyme (TACE/ADAM17), the activation of this protease seems at least in part unaffected by ART. Reaffirming a role of TNF in chronic HIV infection, treatment with TNF inhibitors improves CD4 counts and reduces immune activation (Gallitano et al, 2016, Kumar et al, 2013). …”

“…In addition a direct stimulation of cytokine production has been reported for Vpr, Tat and Nef, however, most of these studies were done with recombinant viral proteins (Kumar et al, 2013). …”