Immunomodulatory Properties of a Viral Homolog of Human Interleukin-10 Expressed by Human Cytomegalovirus during the Latent Phase of Infection

Abstract

Human cytomegalovirus (HCMV) establishes a latent infection in hematopoietic cells, from which it can reactivate to cause significant disease in immunocompromised individuals. HCMV expresses a functional homolog of the immunosuppressive cytokine interleukin-10 (termed cmvIL-10), and alternate splicing of the cmvIL-10 transcript results in expression of a latency-associated cmvIL-10 transcript (LAcmvIL-10). To determine whether LAcmvIL-10 encodes immunosuppressive functions, recombinant LAcmvIL-10 protein was generated, and its impact on major histocompatibility complex class II (MHC-II) expression was examined on granulocyte macrophage progenitor cells (GM-Ps) and monocytes. LAcmvIL-10 (and cmvIL-10) downregulated MHC-II on the surfaces of both cell types. This downregulation was associated with a decrease in total MHC-II protein and transcription of components of the MHC-II biosynthesis pathway. Unlike cmvIL-10, LAcmvIL-10 did not trigger phosphorylation of Stat3, and its ability to downregulate MHC-II was not blocked by neutralizing antibodies to the human IL-10 receptor, suggesting that LAcmvIL-10 either does not engage the cellular IL-10 receptor or utilizes it in a different manner from cmvIL-10. The impact of LAcmvIL-10 on dendritic cell (DC) maturation was also assessed. In contrast to cmvIL-10, LAcmvIL-10 did not inhibit the expression of costimulatory molecules CD40, CD80, and CD86 and the maturation marker CD83 on DCs, nor did it inhibit proinflammatory cytokines (IL-1␣, IL-1␤, IL-6 and tumor necrosis factor alpha). Thus, LAcmvIL-10 retains some, but not all, of the immunosuppressive functions of cmvIL-10. As GM-Ps and monocytes support latent infection, expression of LAcmvIL-10 may enable HCMV to avoid immune recognition and clearance during latency.

Mechanisms modulating immune clearance during human cytomegalovirus latency

“…This report (3) also highlights the role of human (h)IL-10, which adds to previous studies that focused on virus-encoded IL-10 expressed during latency (17,(22)(23)(24). On the one hand, viral IL-10 may induce hIL-10.…”

Koi Herpesvirus Encodes and Expresses a Functional Interleukin-10

“…In contrast, HCMV-encoded IL-10 (cmvIL-10) shares quite low sequence identity with human IL-10 but also functions via the IL-10R receptor, to which it binds strongly, and, like human IL-10, triggers the Jak1/STAT3 pathway (27,29,50). Also, unlike other viral IL-10s, HCMV IL-10 transcripts occur as two major splice variants, cmvIL-10 and LAcmvIL-10, the latter of which is expressed during latent and productive phases of infection and does not appear to share the full range of immunomodulatory functions of cmvIL-10 (25,26,49).…”

The immunology of human cytomegalovirus latency: could latent infection be cleared by novel immunotherapeutic strategies?

“…63 Similarly, a latency-associated splice product of UL111A encodes a viral IL-10 homologue (LAvIL-10) and acts to downregulate MHC Class II expression on experimentally latently infected myeloid cells and this modulates CD4 1 T-cell recognition. 20,64,65 UL144 has sequence similarity with members of the tumour-necrosis factor receptor superfamily, [66][67][68] as well as the herpes simplex virus entry mediator. However, UL144 is unlikely to act as a decoy TNF receptor and there is no evidence that UL144 binds TNF.…”