Virus-Encoded Homologs of Cellular Interleukin-10 and Their Control of Host Immune Function

Abstract

The capacity of viruses to successfully infect the immunocompetent host to cause disease argues in favor of virus-encoded functions that specifically target components of the immune system so as to orchestrate an environment that limits the capacity of the host immune response to clear infection. In this respect, many viruses have evolved to coexist with the host immune system by developing an arsenal of strategies to avoid immune surveillance and elimination from the host. These include viruses which have acquired homologs of cellular cytokines or cytokine receptors as a strategy to limit host immune recognition. Cellular interleukin-10 (IL-10) is a pleiotropic immunomodulatory cytokine produced by a wide variety of cells, including monocytes, macrophages, T and B lymphocytes, dendritic cells (DC), keratinocytes, epithelial cells, and mast cells. The properties of IL-10 have been comprehensively reviewed elsewhere (12, 69, 70, 72, 77) and so will not be covered in detail here, but the key features of this cytokine relate mainly to its capacity to exert potent immunosuppressive functions on the expression of a range of cytokines and chemokines (2, 16, 23), as well as the repression of major histocompatibility complex (MHC) molecules and costimulatory molecules (17, 104) and the maturation and function of DC (69). The immunosuppressive properties of IL-10 are primarily restricted to cells of the myeloid lineage (69). In contrast, IL-10 has been shown to exert a stimulatory effect on B lymphocytes (15, 28, 87), mast cells (99), thymocytes (64), and CD8+ T cells (31, 88, 90), highlighting the cell-type-dependent immunomodulatory properties of this cytokine. The immunomodulatory functions manifested by IL-10 require engagement of this cytokine with its cell surface bound receptor. The IL-10 receptor (IL-10R) consists of two different subunits (IL-10R1 and IL-10R2) (52, 60). IL-10 binds first to IL-10R1 with high affinity, and the resulting intermediate IL-10/IL-10R1 complex then binds with lower affinity to IL-10R2. The resulting active signaling complex induces the JAK/Stat signal transduction pathway (69, 72). In the context of viral pathogenesis, infections with a number of different viruses have been documented to upregulate the expression of IL-10, and in some cases, this upregulation has been shown to enhance infection by suppressing the immune function, suggesting that the far-reaching effects of this cytokine have many advantages for invading pathogens (3, 4, 18, 30, 45, 81, 82, 108, 111). IL-10-like open reading frames (ORF) have been identified by sequence homology in multiple members of the Herpesvirales and Poxviridae, all but one of which infect mammalian hosts (Table ​(Table1).1). The one exception, cyprinid herpesvirus 3, is a member of the Alloherpesviridae family of herpesviruses (order, Herpesvirales), which has the common carp (Cyprinus carpio) as its normal host (1). Otherwise, all of the herpesviruses identified to date as encoding IL-10-like ORF, including human cytomegalovirus (HCMV) and Epstein-Barr virus (EBV), are found only in the Beta- and Gammaherpesvirinae subfamilies of the Herpesviridae. No examples of the Alphaherpesvirinae that encode IL-10 homologs have been identified. Of the identified members of the Herpesviridae that encode IL-10 homologs, all but two, equid herpesvirus 2 and ovine herpesvirus 2 (OvHV2) (85, 96, 97), are confined to primate hosts (Table ​(Table1).1). All of the identified Poxviridae that encode IL-10 infect ruminants, including orf virus ([ORFV] sheep and goats), sheeppox virus ([SPPV] sheep), goatpox virus ([GPV] goats), and lumpy skin disease virus ([LSDV] cattle). The genomes of SPPV, GPV, and LSDV are 96 to 97% identical at the nucleic acid level (48, 101). Another member of the Poxviridae that has monkeys as its normal host, yaba-like disease virus, encodes an ORF (Y134R) that exhibits sequence homology to the IL-10-related cytokines IL-19, IL-20, and IL-24 (57). These viral IL-10 (vIL-10) homologs range in size from 139 to 191 amino acids (aa), bracketing the range in sizes for cellular IL-10 proteins (176 to 180 aa). TABLE 1. Viruses with IL-10-like or IL-10-related ORF The role of virus-encoded IL-10 homologs is likely to provide a tool to enable modulation of the local immune response so as to enhance the capacity to replicate, disseminate, and/or persist in an otherwise immunocompetent individual. In fact, there is emerging evidence that virus-encoded IL-10 homologs function in this capacity in a variety of settings. This review will cover those viruses which have thus far been identified as encoding homologs of IL-10. The similarities of each homolog to the IL-10 of the natural host species will be presented together with their biological functions (where known) and the role they may play in viral pathogenesis and evasion of the host immune response.