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Journal of Virology, April 2008, p. 3736-3750, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.02173-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.

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

C. Jenkins,1 W. Garcia,1 M. J. Godwin,1 J. V. Spencer,3 J. Lewis Stern,1 A. Abendroth,1,2,{dagger} and B. Slobedman1,{dagger}*

Centre for Virus Research, Westmead Millennium Institute and University of Sydney, Westmead, New South Wales 2145, Australia,1 Department Infectious Diseases and Immunology, University of Sydney, New South Wales 2006, Australia,2 University of San Francisco, San Francisco, California 941173

Received 4 October 2007/ Accepted 11 January 2008

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{alpha}, IL-1β, 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.

* Corresponding author. Mailing address: Centre for Virus Research, Westmead Millennium Institute, P.O. Box 412, Westmead, NSW 2145, Australia. Phone: 61 2 98459122. Fax: 61 2 98459100. E-mail: barry_slobedman{at}wmi.usyd.edu.au

{triangledown} Published ahead of print on 23 January 2008.

{dagger} A.A. and B.S. contributed equally to this work.

Journal of Virology, April 2008, p. 3736-3750, Vol. 82, No. 7
0022-538X/08/$08.00+0     doi:10.1128/JVI.02173-07
Copyright © 2008, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Cheung, A. K. L., Gottlieb, D. J., Plachter, B., Pepperl-Klindworth, S., Avdic, S., Cunningham, A. L., Abendroth, A., Slobedman, B. (2009). The role of the human cytomegalovirus UL111A gene in down-regulating CD4+ T-cell recognition of latently infected cells: implications for virus elimination during latency. Blood 114: 4128-4137 [Abstract] [Full Text]  
  • Slobedman, B., Barry, P. A., Spencer, J. V., Avdic, S., Abendroth, A. (2009). Virus-Encoded Homologs of Cellular Interleukin-10 and Their Control of Host Immune Function. J. Virol. 83: 9618-9629 [Full Text]  


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