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, Roman A. Tomazin, Todd W. Wisner, Claire Dunn, Jessica M. Boname, David Lewinsohn, David Johnson

Research output: Contribution to journalArticle

82 Citations (Scopus)

Abstract

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-α and -DM-α 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 α/β 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.

Original languageEnglish (US)
Pages (from-to)10929-10941
Number of pages13
JournalJournal of Virology
Volume76
Issue number21
DOIs
StatePublished - Nov 2002

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Human herpesvirus 5
antigen presentation
Histocompatibility Antigens Class II
Antigen Presentation
major histocompatibility complex
HLA Antigens
Major Histocompatibility Complex
Cytomegalovirus
glycoproteins
Glycoproteins
T-lymphocytes
T-Lymphocytes
CD4 Antigens
Endoplasmic Reticulum
endoplasmic reticulum
immune evasion
antigens
Immune Evasion
Histocompatibility Antigens Class I
Golgi Apparatus

ASJC Scopus subject areas

  • Immunology

Cite this

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. / Hegde, Nagendra R.; Tomazin, Roman A.; Wisner, Todd W.; Dunn, Claire; Boname, Jessica M.; Lewinsohn, David; Johnson, David.

In: Journal of Virology, Vol. 76, No. 21, 11.2002, p. 10929-10941.

Research output: Contribution to journalArticle

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abstract = "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-α and -DM-α 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 α/β 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.",
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