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Journal of Virology, November 2002, p. 10929-10941, Vol. 76, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.21.10929-10941.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Inhibition of HLA-DR Assembly, Transport, and Loading by Human Cytomegalovirus Glycoprotein US3: a Novel Mechanism for Evading Major Histocompatibility Complex Class II Antigen Presentation

Nagendra R. Hegde,1 Roman A. Tomazin,1 Todd W. Wisner,1 Claire Dunn,1 Jessica M. Boname,2 David M. Lewinsohn,3 and David C. Johnson1*

Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, Oregon 97239,1 Department of Pathology, Cambridge University, Cambridge, United Kingdom,2 Division of Pulmonary and Critical Care Medicine, Portland Veterans Affairs Medical Center, Portland, Oregon 972073

Received 3 May 2002/ Accepted 17 July 2002

Human cytomegalovirus (HCMV) establishes persistent lifelong infections and replicates slowly. To withstand robust immunity, HCMV utilizes numerous immune evasion strategies. The HCMV gene cassette encoding US2 to US11 encodes four homologous glycoproteins, US2, US3, US6, and US11, that inhibit the major histocompatibility complex class I (MHC-I) antigen presentation pathway, probably inhibiting recognition by CD8+ T lymphocytes. US2 also inhibits the MHC-II antigen presentation pathway, causing degradation of human leukocyte antigen (HLA)-DR-{alpha} and -DM-{alpha} and preventing recognition by CD4+ T cells. We investigated the effects of seven of the US2 to US11 glycoproteins on the MHC-II pathway. Each of the glycoproteins was expressed by using replication-defective adenovirus vectors. In addition to US2, US3 inhibited recognition of antigen by CD4+ T cells by a novel mechanism. US3 bound to class II {alpha}/ß complexes in the endoplasmic reticulum (ER), reducing their association with Ii. Class II molecules moved normally from the ER to the Golgi apparatus in US3-expressing cells but were not sorted efficiently to the class II loading compartment. As a consequence, formation of peptide-loaded class II complexes was reduced. We concluded that US3 and US2 can collaborate to inhibit class II-mediated presentation of endogenous HCMV antigens to CD4+ T cells, allowing virus-infected cells to resist recognition by CD4+ T cells.

* Corresponding author. Mailing address: Mail code L-220, Rm. 6383 BSc, Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR 97239-3098. Phone: (503) 494-0834. Fax: (503) 494-6862. E-mail: johnsoda{at}ohsu.edu.

Journal of Virology, November 2002, p. 10929-10941, Vol. 76, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.21.10929-10941.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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