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.

Figure 1

TNF and TNFR superfamily-mediated cell signaling. Binding of TNF-alpha to TNFRs results in activation of its receptors followed by recruitment of adaptor proteins (TRADD, FADD, TRAF, and RIP) in sequential manner that activates several signaling cascades leading to the activation of transcription factors NF-kappaB, AP-1, and/or caspase cascades. Most of the members of TNF superfamily activate also NF-kappaB.

Figure 2

TNF signaling mimicking by HIV proteins. Early expressed HIV proteins Vpr, Tat, and Nef mimic TNF-alpha as they activate TNF-alpha governing signaling pathways to enhance HIV replication in infected cells.

Figure 3

4-1BB and OX40 signaling enhance anti-HIV immunity, leading to therapeutic effects. Agonists 4-1BB or OX40 specific antibodies can induce enhanced anti-HIV T cell (CD4+ and CD8+ T cell) response in HIV-1 infected patients. The ligation of OX40/4-1BB antibodies activates OX40/4-1BB signaling that results in enhanced CD4+ T cell response through increased cytokine production and increased survival of memory T cells. TRAFs and NF-kappaB signaling has been shown to be important for the generation of memory T cells. Potential antiviral mechanisms of OX40/4-1BB include an increase in CD8+ T cell cytotoxicity through perforins and granzymes and an increase in Fas/FasL mediated HIV-infected cell killing.

Figure 4

Potential TNF-based therapies to reactivate HIV-1 from latency. During HIV-1 latency, nuc-1 nucleosome is hypoacetylated. CTIP-2 interacts with Sp1, switching nuc-1 from transcriptionally active to a repressive state. Furthermore, CTIP-2 recruits HDACs that deacetylate the nuc-1 nucleosome. SUV39H1 adds trimethylation mark onto the histone protein H3. Furthermore, HP1 protein stabilizes the nuc-1 in transcriptionally silent state. The combination of TNF-alpha with HDACIs or HMTIs can disrupt the HIV-1 latency. TNF-alpha and HDACIs can trigger the activation of transcriptional activators, such as NF-kappaB (p50/p65 heterodimer). HDACIs may prevent the formation of heterochromatin, resulting in nuc-1 hyperacetylation and remodeling, thereby alleviating the HIV transcriptional block. The use of TNF, HDACIs, and HMTIs enhances HIV-1 LTR transcription and could participate in the clearance of HIV-1 from cellular reservoirs and ultimately could lead to the cure of HIV-infected patients.