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. 2000 Feb;74(4):1900-7.
doi: 10.1128/jvi.74.4.1900-1907.2000.

Modulation of major histocompatibility class II protein expression by varicella-zoster virus

A Abendroth  1 , B Slobedman, E Lee, E Mellins, M Wallace, A M Arvin
Affiliations

Modulation of major histocompatibility class II protein expression by varicella-zoster virus

A Abendroth et al. J Virol. 2000 Feb.

Abstract

We sought to investigate the effects of varicella-zoster virus (VZV) infection on gamma interferon (IFN-gamma)-stimulated expression of cell surface major histocompatibility complex (MHC) class II molecules on human fibroblasts. IFN-gamma treatment induced cell surface MHC class II expression on 60 to 86% of uninfected cells, compared to 20 to 30% of cells which had been infected with VZV prior to the addition of IFN-gamma. In contrast, cells that were treated with IFN-gamma before VZV infection had profiles of MHC class II expression similar to those of uninfected cell populations. Neither IFN-gamma treatment nor VZV infection affected the expression of transferrin receptor (CD71). In situ and Northern blot hybridization of MHC II (MHC class II DR-alpha) RNA expression in response to IFN-gamma stimulation revealed that MHC class II DR-alpha mRNA accumulated in uninfected cells but not in cells infected with VZV. When skin biopsies of varicella lesions were analyzed by in situ hybridization, MHC class II transcripts were detected in areas around lesions but not in cells that were infected with VZV. VZV infection inhibited the expression of Stat 1alpha and Jak2 proteins but had little effect on Jak1. Analysis of regulatory events in the IFN-gamma signaling pathway showed that VZV infection inhibited transcription of interferon regulatory factor 1 and the MHC class II transactivator. This is the first report that VZV encodes an immunomodulatory function which directly interferes with the IFN-gamma signal transduction via the Jak/Stat pathway and enables the virus to inhibit IFN-gamma induction of cell surface MHC class II expression. This inhibition of MHC class II expression on VZV-infected cells in vivo may transiently protect cells from CD4(+) T-cell immune surveillance, facilitating local virus replication and transmission during the first few days of cutaneous lesion formation.

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Figures

FIG. 1
FIG. 1
FACS analysis of MHC class II, transferrin receptor (CD71), and VZV proteins on VZV-infected cells treated with IFN-γ. HFF were, at 12 h after VZV infection, treated with IFN-γ for 36 h (A and B) or were treated with IFN-γ for 36 h and then infected with VZV (D and E); cell preparations were stained with antibodies and fluorescent conjugates to MHC class II and VZV proteins (A and D) or to transferrin receptor and VZV proteins (B and E). The percentage of VZV+ and VZV− cell populations expressing cell surface MHC class II is shown with VZV infection and subsequent IFN-γ treatment (C) and IFN-γ treatment followed by VZV infection (F).
FIG. 2
FIG. 2
Detection of MHC class II DR-α and CD71 mRNA by Northern blot hybridization in VZV-infected cells treated with IFN-γ. Northern blot hybridization for MHC class II DR-α (A) and CD71 (B) was performed on total cell RNA extracted from 8.1.6 cells (lane 1), uninfected HFF (lane 2), uninfected HFF treated with IFN-γ (lane 3), VZV-infected HFF (lane 4), and HFF exposed to VZV, treated with IFN-γ, and sorted by FACS into VZV− (lane 5) and VZV+/MHC class II DR− (lane 6) cell populations.
FIG. 3
FIG. 3
Detection of MHC class II DR-α RNA and VZV IE62 RNA by in situ hybridization in VZV-infected cells stimulated with IFN-γ. VZV-infected cells treated with IFN-γ were antibody stained and FACS sorted into two populations: VZV− (A and D) and VZV+/MHC class II DR− (B and C); cells were then hybridized with strand-specific DIG-labeled riboprobes to MHC class II DR-α transcripts (A and B) and VZV IE62 transcripts (C and D).
FIG. 4
FIG. 4
MHC class II DR-α and VZV IE62 RNA expression in cutaneous varicella skin lesions. Biopsies of skin lesions from subjects with varicella were sectioned and hybridized with strand-specific DIG labeled riboprobes to VZV IE62 transcripts (A) and MHC class II DR-α transcripts (B and C). Positive hybridization for VZV IE62 was detected in the lesion and deeper in the dermis (black arrows), whereas MHC class II DR-α was detected in areas of infiltrating cells (boxed area) adjacent to VZV+ cells.
FIG. 5
FIG. 5
Analysis of CIITA and IRF-1 RNA expression in VZV-infected IFN-γ-treated cells. (A) RT-PCR for CIITA and CD71 was performed on total cell RNA extracted from VZV-infected HFF treated with IFN-γ, antibody stained, and sorted by FACS into VZV− (lanes 2 and 3) and VZV+/MHC class II DRα− (lanes 4 and 5). No DNA was included as a PCR control (lane 1); no-RT control for each sample is shown in lanes 3 and 5. (B) Northern blot hybridization for IRF-1 was performed on total cell RNA extracted from 8.1.6 cells (lane 1), uninfected HFF (lane 2), uninfected HFF treated with IFN-γ (lane 3), VZV-infected HFF (lane 4), and VZV-infected HFF treated with IFN-γ, antibody stained, and sorted by FACS into VZV− (lane 5) and VZV+/MHC class II DR-α− (lane 6) cell populations.
FIG. 6
FIG. 6
Detection of Jak1, Jak2, Stat 1α, and CD71 protein expression by Western blot analysis in VZV-infected IFN-γ-treated cells. Protein lysates were obtained from VZV-infected HFF treated with IFN-γ, antibody stained, and sorted by FACS into VZV− (lane 2) and VZV+/MHC class II DR-α− (lane 3) cell populations. The positive control consisted of mock-infected HFF treated with IFN-γ for 48 h (lane 1). Membranes were incubated with antibodies to Jak1, Jak2, Stat 1α, and CD71, and bound antibodies were visualized by ECL.
FIG. 7
FIG. 7
Schematic diagram of the sites of VZV-mediated disruption of IFN-γ-induced MHC class II expression. The various proteins that are affected in VZV-infected cells are crossed out.
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