Human cytomegalovirus infection interferes with major histocompatibility complex type II maturation and endocytic proteases in dendritic cells at multiple levels

Abstract

Human cytomegalovirus (HCMV) infection suppresses cellular immunity and results in viral persistence. Dendritic cells (DCs) are susceptible to HCMV, and the development and immune function of HCMV-infected DCs are impaired in vitro. HCMV-derived proteins interfere with different aspects of major histocompatibility complex type II (MHC II) maturation and function in genetically engineered cellular models. This study directly analysed the effect of HCMV on the MHC II-associated antigen processing and presentation machinery in HCMV-infected human DCs in vitro. HCMV-infected DCs failed to mature newly synthesized MHC II to the final stage of SDS-stable MHC II ab dimer/peptide complexes, in contrast to mock-infected controls. MHC II biosynthesis was delayed and reduced, whilst MHC II stability remained unchanged. MHC II surface expression was decreased in the late phase of HCMV infection. In addition, infected DCs decreased the transcription rate of the MHC II-associated proteases cathepsins S, Z, B, H and L and asparagine-specific endopeptidase (AEP). This translated into reduced protein expression of cathepsins H and S, as well as AEP, and less-efficient proteolytic degradation of a peptide substrate by endocytic proteases from HCMV-infected DCs in vitro. Thus, HCMV infection interferes with MHC II biosynthesis and maturation, as well as with the expression and function of endocytic proteases in infected DCs.

Protease Cleavage Sites in HIV-1 gp120 Recognized by Antigen Processing Enzymes Are Conserved and Located at Receptor Binding Sites

“…Previous studies have suggested that many viruses, including HIV, have evolved mechanisms to alter antigen processing to their advantage, as a way to escape or direct the immune response (103). Most of these mechanisms affect MHC class I-restricted cellular immune responses; however, mechanisms that alter MHC class II antigen presentation have also been reported (54).…”

Cytomegalovirus Expresses the Chemokine Homologue vXCL1 Capable of Attracting XCR1 + CD4 − Dendritic Cells

“…Infection of DC was shown to be accompanied by reduced surface expression of MHC-I and -II molecules (50)(51)(52), altered cytokine and chemokine receptor expression (53), and downregulation of molecules required for T and NK cell proliferation (48,50,52). Since DC are important for regulating and controlling T and NK cell responses (54,55) and the latter play a major role in controlling CMV infection (56-60), MuHV8 might infect and functionally paralyze this DC subset by vXCL1 attraction in order to impair antiviral responses.…”

NKp46 and DNAM-1 NK-cell receptors drive the response to human cytomegalovirus-infected myeloid dendritic cells overcoming viral immune evasion strategies

“…18 Infection of moDCs has been reported to impair their maturation, inhibiting surface expression of major histocompatibility complex class I and II, costimulatory molecules, and chemokine receptors (ie, CCR1 and CCR5), thus interfering with the development of virus-specific T-cell responses. [19][20][21] Beyond their key role in antigen presentation, DCs may establish a cross-talk with NK cells that reciprocally regulates their Submitted August 9, 2010; accepted October 13, 2010. Prepublished online as Blood First Edition paper, October 28, 2010; DOI 10.1182 DOI 10.…”

“…19,20 Inhibition of HLA class I expression is known to be mediated by US2, US3, US6, and US11, 3 whereas the mechanisms underlying the different pattern of HLA class II down-regulation are more complex. 19 The proportion of cells displaying a reduced expression of HLA class I molecules correlated with the number of IE-1/IE-2 ϩ cells in all experiments, and time course analysis revealed that the inhibition of HLA-I expression was detectable at 48 hours (data not shown). The noninfected moDC subset in TB40/E treated cultures, as well as cells incubated with UV-inactivated TB40/E, expressed higher levels of HLA class I molecules than mock moDCs, an effect attributed to the endogenous production of type I IFN-␣, according to previous reports.…”