Chemokines encoded by herpesviruses

Abstract

Viruses use diverse strategies to elude the immune system, including copying and repurposing host cytokine and cytokine receptor genes. For herpesviruses, the chemokine system of chemotactic cytokines and receptors is a common source of copied genes. Here, we review the current state of knowledge about herpesvirus-encoded chemokines and discuss their possible roles in viral pathogenesis, as well as their clinical potential as novel anti-inflammatory agents or targets for new antiviral strategies.

Keywords: Chemotaxis; chemokine receptors; immune evasion; viral chemokine.

Figure 1.. CMV syntenic chemokines.

(A) Schematic representation of the genomic distribution of viral chemokines in a syntenic region of the genomes of HCMV (Toledo strain), MCMV (Smith strain), and RCMV (English and Maastricht strains). Gray boxes correspond to nonchemokine ORFs; blue boxes indicate viral ORFs with CC chemokine homology. UL130 ORF, a C chemokine, is represented as an orange box. Splicing events are shown as connecting lines between boxes. CC chemokine names that differ from that of the ORF are indicated below the protein products (black arrows). (B) Models of viral envelope cell-entry complexes of HCMV Toledo and MCMV Smith containing viral chemokine homologs. Crossed lines and dots between proteins indicate covalent and noncovalent interactions, respectively. The HCMV diagram represents a combination of the protein–protein interactions proposed in the literature for this pentamer [–46]. The MCMV diagram represents a trimeric protein complex based on the studies of Wagner et al. [76], who showed that the MCK-2 from MCMV Smith interacts with the gH/gL envelope dimer. The nature of the protein–protein interactions of gH/gL/MCK-2 has not been delineated yet. Blue phospholipid bilayers represent the viral envelope.

Figure 2.. Human and HHV-encoded chemokine phylogeny.

Maximum-likelihood phylogenetic analysis of human chemokines and chemokines expressed by HHVs using SeaView [228]. Alignment gaps were excluded from the analysis. Viral chemokines (UL128, gene UL128, HCMV strain AD169, UniProt Accession No. P16837; vCCL1, gene K6, KSHV isolate GK18, UniProt Accession No. F5HET8; vCCL2, gene K4, KSHV isolate GK18, UniProt Accession No. Q98157; vCCL3, gene K4.1, KSHV isolate GK18, UniProt Accession No. F5HCJ2; vCCL4a, gene U83, HHV-6A strain U1102, UniProt Accession No. P52460; vCCL4b, gene U83, HHV-6B strain Z29, UniProt Accession No. P52461; vCXCL1, gene UL146, HCMV strain Merlin, UniProt Accession No. F5HBX1; vCXCL2, gene UL147, HCMV strain Toledo, UniProt Accession No. Q68399) are highlighted in blue, and their amino acid identities to the most closely related human chemokine are indicated in the right column. Of note, vCXCL1 and vCXCL2 display high strain-to-strain variability; therefore, the phylogeny of chemokines from other HCMV strains might differ from the one presented here.

Figure 3.. Model of action of spliced and full-length vCCL4a during HHV-6A infection.

HHV-6A vCCL4a is differentially regulated by splicing during the distinct phases of viral infection. A truncated chemokine (spliced vCCL4a) is expressed independently from viral replication during the early lytic phase or latency, whereas full-length vCCL4a is accumulated when active viral replication occurs (late lytic phase). Both spliced and full-length vCCL4a interact with the same chemokine receptors (CCR1, CCR5, CCR4, and CCR8) but acting as antagonist or agonist, respectively. This may allow a selective control of immune cell migration, selectively benefiting distinct phases of the infection. During the early lytic phase, spliced vCCL4a may inhibit the recruitment of immune cells to facilitate the completion of the viral lytic cycle. Then, the full-length chemokine may attract lymphocytes for lytic or latent infection and subsequent viral dissemination, while recruiting CCR4- and CCR8-bearing Th2 cells that dampen the antiviral activity of Th1 cells recruited by the chemokine through CCR1 or CCR5. Once latency has been established (episomal HHV-6), the immune response may be inhibited by re-expression of spliced vCCL4a, shielding the silent state of the chronic infection. This model is based on the studies published by French et al. [136] and Dewin et al.[143].

Figure 4.. Bioactivities of herpesvirus-encoded chemokines to support viral infection.

Summary of the agonistic (green arrows) or antagonistic (red arrows) potential activities of viral chemokines whose cellular receptors have been identified. Herpesviruses may express chemokine homologs to manipulate the migration patterns of different cell types with 3 major goals: 1) to skew the immune response from Th1 to Th2 by attracting Th2 cells (vCCL1, vCCL2, and vCCL4a) or by blocking the recruitment of Th1 cells (vCCL2); 2) to promote viral dissemination by recruiting target cells (neutrophils, lymphocytes, macrophages, DCs, etc.); and 3) to facilitate the establishment of chronic infections by attracting cell types that support viral latency, such as macrophages (vCCL4b) or DCs (vXCL1 and vCCL3). Chemokines are color coded to indicate the corresponding HHVs (see “key”) in each case.