Chemokine-binding proteins encoded by herpesviruses

Abstract

To establish infection, a wide variety of pathogens, including viruses, have evolved a number of strategies to avoid immune elimination. Viruses have acquired and optimized molecules that interact with the host chemokine network in order to disrupt immune surveillance and defense of vertebrates, helping to promote cell entry, facilitating dissemination of infected cells, and evasion the immune response. Viral immunomodulators include ligands, chemokine receptors and chemokinebinding proteins (vCKBPs) functioning as either cell surface receptor mimics, ligand mimics, or secreted chemokine-binding proteins. vCKBPs specifically modulate chemokine gradient formation and ligandreceptor recognition when they have a potential to even completely block chemokine-mediated responses to viral infection. Members of only two virus families (Herpesviridae and Poxviridae) encode vCKBPs capable of sequestering host chemokines through either the chemokine receptor, GAG-binding pocket, or both, which may result in the inhibition of chemotaxis in vivo. Here, we focused on vCKBPs encoded by α-, β-, and γ-herpesviruses, of which several have been experimentally used as anti-inflammatory or anti-immune reagents in animal models. Current results suggest that vCKBPs could be used to regulate the activity of both chemokines and chemokine receptors for the treatment of infections such as AIDS, diseases such as arthritis, neurotrauma, inflammatory CNS disorders, atherosclerosis, transplant rejection, and metastatic spread and angiogenesis. Better understanding of vCKBPs biology will help evaluate, which human diseases related to chemokine network dysregulation might be effectively treated with these novel promising immunomodulatory drugs to enable the manipulation of chemokine functions and leukocyte trafficking.

Virus-Derived Chemokine Modulating Protein Pre-Treatment Blocks Chemokine–Glycosaminoglycan Interactions and Significantly Reduces Transplant Immune Damage

“…We have developed virus-derived immune-modulating proteins as a new class of therapeutic. M-T7 is a 37 KDa myxoma virus-derived purified protein that binds C, CC and CXC classes of chemokines, blocking chemokine to GAG binding [ 7 , 8 , 9 , 10 , 11 ]. In prior studies, modifying chemokine and chemokine receptor activity reduced transplant damage and rejection [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ].…”

“…M-T7 is a 37 KDa myxoma virus-derived purified protein that binds C, CC and CXC classes of chemokines, blocking chemokine to GAG binding [ 7 , 8 , 9 , 10 , 11 ]. In prior studies, modifying chemokine and chemokine receptor activity reduced transplant damage and rejection [ 8 , 9 , 10 , 11 , 12 , 13 , 14 ]. Treatment after transplant with M-T7 reduced the aortic allograft vascular inflammation at 30 days follow-up [ 8 ].…”

“…Modifying the endothelial polysaccharides and GAG composition also reduced immune cell response and organ damage in a separate series of transplant models, including aortic and renal allograft studies. [ 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

“…Treatment of grafts prior to surgical transplant is postulated to improve graft outcomes by decreasing inflammation and organ damage before transplantation [ 10 , 11 , 12 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 ]. Dopamine pre-treatment of donor organs has demonstrated reduced renal allograft rejection and superior long-term graft survival [ 24 ].…”

Introduction

“…Understanding molecular details of regulatory and/ or structural proteins encoded by viruses are also of high importance as these proteins can affect the course of virus infections at various critical steps. For example, herpesviruses encode chemokine-binding proteins that allow for evasion of the immune defence mechanisms mediated by network of host immunomodulatory molecules, as discussed by Benko et al (2020). These viral chemokines can on one hand facilitate virus infection, but on the other one can be also viewed as potential antiinflammatory or immunomodulatory drugs.…”