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Journal of Virology, February 2009, p. 1359-1367, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01324-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Human Cytomegalovirus-Encoded Immune Modulators Partner To Downregulate Major Histocompatibility Complex Class I Molecules {triangledown} ,{dagger}

Vanessa M. Noriega and Domenico Tortorella*

Department of Microbiology, Mount Sinai School of Medicine, New York, New York 10029

Received 24 June 2008/ Accepted 4 November 2008

Throughout the course of natural evolution with its host, the human cytomegalovirus (HCMV) has developed a variety of strategies to avoid immune recognition and clearance. The major histocompatibility complex (MHC) class I antigen presentation pathway is a major target of the virus. HCMV encodes at least six gene products that modulate the processing of endoplasmic reticulum (ER)-resident MHC class I molecules. Here, we show that two virus-encoded proteins, US2 and US3, coordinate their functions toward the common goal of attenuating class I protein surface expression. In cells stably expressing both US2 and US3, class I molecules were almost completely downregulated from the cell surface. In addition, pulse-chase analysis revealed that the proteasome-dependent turnover of class I molecules occurs more rapidly in cells expressing both US2 and US3 than either US2 or US3 alone. The ability of US3 to retain class I molecules in the ER produces a target-rich environment for US2 to mediate the destruction of class I heavy chains. In fact, expression of US3 enhanced the association between US2 and class I molecules, thus encouraging their dislocation and degradation. This immune evasion strategy ensures that viral antigens are not presented on the cell surface during the early phase of HCMV infection, a critical time of replication and viral proliferation.

* Corresponding author. Mailing address: One Gustave L. Levy Place, Box 1124, New York, NY 10029. Phone: (212) 241-5447. Fax: (212) 241-7336. E-mail: Domenico.Tortorella{at}mssm.edu

{triangledown} Published ahead of print on 12 November 2008.

{dagger} Supplemental material for this article may be found at http://jvi.asm.org/.

Journal of Virology, February 2009, p. 1359-1367, Vol. 83, No. 3
0022-538X/09/$08.00+0     doi:10.1128/JVI.01324-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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