Modulation of Major Histocompatibility Class II Protein Expression by Varicella-Zoster Virus

Abstract

We sought to investigate the effects of varicella-zoster virus (VZV) infection on gamma interferon (IFN-␥Major histocompatibility complex (MHC) class II molecules are highly polymorphic heterodimers consisting of an ␣ and ␤ chain which present exogenous peptides to CD4 ϩ T lymphocytes. The ␣ and ␤ chains form a heterodimer in the endoplasmic reticulum, and this complex, when associated with the invariant chain (Ii), is transported through the Golgi and transGolgi reticulum to cytosolic endosomes. At this site, limited Ii chain proteolysis occurs and results in a complex of ␣␤ with Ii-derived peptides, termed CLIPs (class II invariant-chain peptides). At an endosomal site, CLIP is exchanged for antigenic peptides derived by proteolysis of endocytosed proteins, a process which is improved by HLA-DM molecules. The peptide-loaded MHC class II molecule is then presented on the cell surface (10,39,42). Constitutive expression of cell surface MHC class II is restricted to specialized cell types including B cells, monocytes, dendritic cells, and those of thymic epithelium, yet gamma interferon (IFN-␥) has been shown to be a potent inducer of MHC class II expression on many cell types, including fibroblasts (14, 44).Varicella-zoster virus (VZV) is a human herpesvirus that causes varicella (chickenpox) as the primary infection in susceptible individuals, establishes latency in sensory ganglia, and may reactivate as herpes zoster (shingles) (4, 13). Multiple components of the innate and antigen-specific immune responses are activated during the course of primary VZV infection. The early host responses to VZV are nonspecific and involve natural killer cells and interferons which function to restrict virus replication and spread (2, 3, 51). VZV-specific T-cell recognition is critical for host recovery from varicella, and both MHC class I-restricted CD8 ϩ and MHC class IIrestricted CD4 ϩ T cells are sensitized during primary VZV infection. VZV-specific CD4 ϩ T cells that are elicited during primary infection are predominantly of the Th1 type (7, 54) and function to produce high levels of IFN-␥, which potentiates the clonal expansion of VZV-specific T cells (3,26,51). Although the classical cytotoxic T-lymphocyte (CTL) response is mediated by CD8 ϩ T cells that recognize viral peptides in association with MHC class I molecules, VZV-specific CTLs can also exhibit MHC class II (CD4 ϩ )-restricted killing of infected target cells (15,17,19,20,23,25,49). Based on these observations, immunomodulatory mechanisms that limit the initial presentation of VZV peptides by MHC class I or class II pathways are likely to have an important effect on viral pathogenesis.It has been postulated that interference with MHC class II-restricted T-cell recognition may promote viral infection in the host by enabling virus-infected cells to resist a crucial arm of the immune response (38,45). In this respect, several viruses including adenovirus, murine and human cytomegalovirus (MCMV and HCMV), mouse hepatitis virus, human immunodeficiency virus, Kirst...

Influenza A virus abrogates IFN‐γ response in respiratory epithelial cells by disruption of the Jak/Stat pathway

“…In this respect, several viruses have been shown to inhibit IFN-c up-regulation of MHC class II expression [22,[37][38][39]. Influenza A virus-specific T cell recognition is critical for host recovery from illness [40,41].…”

“…HLA-DRa expression is reduced to the same levels seen in unstimulated A549 cells infected with influenza A virus, suggesting that IFN-cinduced induced up-regulation of HLA-DRa expression is totally inhibited. Some viruses specifically target CIITA to inhibit IFN-c-induced MHC class II expression [22,37]. We therefore looked at CIITA transcription by IFN-c in influenza A virus-infected A549 cells.…”

Mini‐review: Specificity and expression of CIITA, the master regulator of MHC class II genes

“…Varizella zoster virus does so by interfering with the IFN-+ signaling pathway. It blocks STAT-1 § and JAK2 expression and therefore transcription of the downstream IRF-1 and CIITA genes [110]. Infection with CMV can direct JAK-1 to the proteasome for degradation or affect the IFN-+ signaling pathway downstream of STAT phosphorylation and nuclear translocation [111,112].…”

“…Varizella zoster virus, human cytomegalovirus (CMV) and human parainfluenza virus type 3 (HPIV3) also inhibit IFN-+ -induced CIITA expression [110][111][112][113]. Varizella zoster virus does so by interfering with the IFN-+ signaling pathway.…”

The Sparing Phenomenon. A case series of the inverse Koebner and related phenomena

“…Thus prolonged repeated continuous ultraviolet radiation might have ability to suppress the ICAM-1 for long period of time. Keratinocytes of patients with lepromatous leprosy lesions were found to lacking in the ICAM-1 expression and the down regulation of ICAM-1 on herpes zoster virus infected keratinocytes are well documented entities in recent literature [13,20,21]. Hence the reduction or inhibition of ICAM-1 induction on keratinocytes by ultraviolet radiation, lepromatous leprosy or herpes zoster virus probably disables the keratinocytes to function as accessory antigen presenting cells and inhibits its role in LFA-1/ICAM-1 Mediated T cell response, and there by prevent the appearance of drug reaction and CTCL on previous skin insult.…”