The power of human cytomegalovirus (HCMV) hijacked UL/b' functions lost in vitro.

Viruses have evolved sophisticated strategies to subvert immunity to benefit overall viral fitness. Human cytomegalovirus (HCMV, ß-herpesvirus) represents a paradigm of very effective hijacking of gene functions that imitate host encoded immunomodulatory proteins. This co-evolution with the host immune system allowed for establishment of lifelong persistence. The HCMV infection is largely asymptomatic in healthy persons; however, it can induce serious disease in immunocompromised individuals. For this reason, great attention is paid to the development of therapeutics based on HCMV immunomodulatory 'tricks' as well as to the search for active vaccine against HCMV. While comparing the HCMV clinical isolates with extensively passaged laboratory strains, the unique long (UL) b' locus was commonly found to be deleted in HCMV genome while adapted to replication in human fibroblasts in vitro. This missing region, called UL/b' region, encodes up to 22 canonical genes with different functions, as of targeting cellular tropism (e.g. UL133-UL138); viral entry and assembly (e.g. UL128, UL130, UL131A); regulation of immunological synapses (e.g. UL135); inhibition of NK and T cell function (e.g. UL141, UL142, UL148, UL144), ablating activity (e.g. UL146, UL147), but mainly aimed at manipulating the host immune response. Moreover, the presence of UL/b' genomic region dramatically correlates with adverse effects in vaccinated persons, indicating that viral genes in this region play a significant role in controlling virulence. Here, we review how HCMV shapes our immunity by hijacked genes originated from UL/b' locus, discuss their impact in immunomodulation mechanism and how this knowledge may translate to clinical applications. Keywords: immunomodulation; HCMV genes; UL/b' locus; NK cell function; HCMV vaccine; immunity; immunotherapeutics.

Chemokine-binding proteins encoded by herpesviruses.

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 chemokine-binding proteins (vCKBPs) functioning as either cell surface receptor mimics, ligand mimics, or secreted chemokine-binding proteins. vCKBPs specifically modulate chemokine gradient formation and ligand-receptor 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-, ß-, 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. Keywords: herpesviruses; chemokine-binding proteins; chemokines; immunomodulation viral infection, chemokines and viral immunomodulators.