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Review
. 2020 Nov 10;9(11):390.
doi: 10.3390/biology9110390.

Lymphotropic Viruses: Chronic Inflammation and Induction of Cancers

Edward W Harhaj  1 , Noula Shembade  2
Affiliations
Review

Lymphotropic Viruses: Chronic Inflammation and Induction of Cancers

Edward W Harhaj et al. Biology (Basel). .

Abstract

Inflammation induced by transcription factors, including Signal Transducers and Activators of Transcription (STATs) and NF-κB, in response to microbial pathogenic infections and ligand dependent receptors stimulation are critical for controlling infections. However, uncontrolled inflammation induced by these transcription factors could lead to immune dysfunction, persistent infection, inflammatory related diseases and the development of cancers. Although the induction of innate immunity and inflammation in response to viral infection is important to control virus replication, its effects can be modulated by lymphotropic viruses including human T-cell leukemia virus type 1 (HTLV-1), Κaposi's sarcoma herpesvirus (KSHV), and Epstein Barr virus (EBV) during de novo infection as well as latent infection. These lymphotropic viruses persistently activate JAK-STAT and NF-κB pathways. Long-term STAT and NF-κB activation by these viruses leads to the induction of chronic inflammation, which can support the persistence of these viruses and promote virus-mediated cancers. Here, we review how HTLV-1, KSHV and EBV hijack the function of host cell surface molecules (CSMs), which are involved in the regulation of chronic inflammation, innate and adaptive immune responses, cell death and the restoration of tissue homeostasis. Thus, better understanding of CSMs-mediated chronic activation of STATs and NF-κB pathways in lymphotropic virus-infected cells may pave the way for therapeutic intervention in malignancies caused by lymphotropic viruses.

Keywords: EBV; HTLV-1; NF-κB; STAT; cancers; cell surface molecules (CSMs); inflammation.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Activation and negative regulation of NF-κB and STAT3. (A) Activation of NF-κB in response to the stimulation of TNFR1, IL-1R, or TLRs. A20 is induced by NF-κB in the TNFR1, IL-1R, or TLRs pathways, functioning as a negative feedback loop. (B) Activation and negative regulation of the STAT3 signaling pathway. The activation of STAT3 is mediated in response to cell surface receptor (growth factor or cytokine receptors) stimulation that leads to the recruitment and activation of the JAK family of kinases, which, in turn, phosphorylate STAT3. Phosphorylated STAT3 dimerize and translocate to the nucleus, where they directly regulate gene expression. This activation loop can be turned off by PIAS and SOCS proteins.
Figure 2
Figure 2
Cell surface molecules-induced STAT3 and NF-κB activation during the early and late phases of infection by lymphotropic viruses. (A) Upon viral (Epstein Barr virus (EBV) or Κaposi’s sarcoma herpesvirus (KSHV)) attachment to cell surface molecules, STAT3 and NF-κB activation, viral entry into target cells, and viral latency establishment occurs. Rapid inflammation induced by STAT3 and NF-κB activation helps to establish viral latency. (B) During viral latency (viral late phase) the viral latent proteins and/or oncogenes, vIL6 and vFLIP of KSHV, LMP1 and BLIF1 of EBV, and Tax and HBZ of human T-cell leukemia virus type 1 (HTLV-1), are expressed. Viral proteins interact with cell surface molecules and maintain chronic activation of STAT3 and NF-κB, essential for EBV, KSHV and HTLV-1 oncogenesis. Viral oncogenes may hijack cell CSMs to inhibit the function of A20 and CylD proteins in NF-κB, and SOCS proteins in STAT3 pathways to maintain chronic activation of NF-κB and STAT3 in lymphotropic virus-infected cells.
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