Varicella zoster virus infection of human fetal lung cells alters mitochondrial morphology.

Varicella zoster virus (VZV) is a ubiquitous alphaherpesvirus that establishes latency in ganglionic neurons throughout the neuraxis after primary infection. Here, we show that VZV infection induces a time-dependent significant change in mitochondrial morphology, an important indicator of cellular health, since mitochondria are involved in essential cellular functions. VZV immediate-early protein 63 (IE63) was detected in mitochondria-rich cellular fractions extracted from infected human fetal lung fibroblasts (HFL) by Western blotting. IE63 interacted with cytochrome c oxidase in bacterial 2-hybrid analyses. Confocal microscopy of VZV-infected HFL cells at multiple times after infection revealed the presence of IE63 in the nucleus, mitochondria, and cytoplasm. Our data provide the first evidence that VZV infection induces alterations in mitochondrial morphology, including fragmentation, which may be involved in cellular damage and/or death during virus infection.

ICP22/IE63 Mediated Transcriptional Regulation and Immune Evasion: Two Important Survival Strategies for Alphaherpesviruses.

In the process of infecting the host, alphaherpesviruses have derived a series of adaptation and survival strategies, such as latent infection, autophagy and immune evasion, to survive in the host environment. Infected cell protein 22 (ICP22) or its homologue immediate early protein 63 (IE63) is a posttranslationally modified multifunctional viral regulatory protein encoded by all alphaherpesviruses. In addition to playing an important role in the efficient use of host cell RNA polymerase II, it also plays an important role in the defense process of the virus overcoming the host immune system. These two effects of ICP22/IE63 are important survival strategies for alphaherpesviruses. In this review, we summarize the complex mechanism by which the ICP22 protein regulates the transcription of alphaherpesviruses and their host genes and the mechanism by which ICP22/IE63 participates in immune escape. Reviewing these mechanisms will also help us understand the pathogenesis of alphaherpesvirus infections and provide new strategies to combat these viral infections.

Antigen-shift in varicella-zoster virus-specific T-cell immunity over the course of Fingolimod-treatment in relapse-remitting multiple sclerosis patients.

BACKGROUND: Fingolimod (FTY) applied as treatment regimen of relapsing-remitting multiple sclerosis (RRMS) induces downregulation of sphingosine-1-phosphate receptors on the lymphocytes. As a result CC chemokine receptor type 7 (CCR7) expressing lymphocytes are retained within the peripheral lymph nodes thus suppressing their accumulation into the cerebrospinal fluid of multiple sclerosis (MS) patients and hampering disease progress. Unfortunately, MS patients treated with FTY suffer from an increased incidence of varicella-zoster virus (VZV) infections which has been associated with a decrease of VZV immediate early 63 (IE63)-specific T-cell immunity. To elucidate VZV-specific T-cell immunity over the course of FTY-treatment, we analyzed T-cell immunity for immediate early, early and late VZV-antigens. METHODS: T-cell immune responses were detected via intracellular IFN-γ staining after stimulation with VZV-specific peptide mixes for IE62 and IE63 and recombinant proteins for open reading frame 26 (ORF26), ORF9 and glycoprotein E (gE) using flow cytometry. Analyzed samples comprised of different groups including 18 patients with RRMS at baseline (BL), 6 and 12 months after FTY-treatment start, 12 patients with long-term (LT) FTY-treatment, one FTY-treated patient, before and after VZV-reactivation. In addition, VZV-specific IgG and IgM titers were assessed by ELISA. RESULTS: After FTY-treatment start, absolute numbers of CCR7 expressing CD4+ T cells and CD8+T cells dropped rapidly. However, VZV-specific immunity could be detected in the majority of RRMS patients throughout FTY-treatment with increasing prevalence after 6 months of treatment. We found an increase in the prevalence of VZV-specific IFN-γ+CD8+ T-cell immunity in FTY-treated patients after six months of therapy, while in parallel VZV-specific IFN-γ+CD4+ T cells declined dramatically. Additionally, a strong correlation between VZV-specific IgG serum titers and the percentage of RRMS patients with detectable VZV-specific T cells was observed (r = 0.985). Most remarkably, FTY-treated RRMS patients presented a shift in the predominant CD8+ T cell-mediated antigen-response from immediate early (IE62) to early virus antigens (ORF26) six months after treatment in parallel to a decrease of VZV-specific CD4+ T-cell immunity. ORF26-specific CD8+ T cells still dominated the VZV-specific cellular immunity at month 12 after FTY-treatment start and in LT FTY-treated MS patients. In a RRMS patient an increase of VZV-specific CD4+ T cells at VZV-reactivation accompanied with a four-fold increase of a VZV-specific IgG titer was detected which might indicate an important role in cellular immune control of VZV-infections. CONCLUSION: Monitoring VZV-specific T-cell immunity might provide a valuable tool to RRMS patient risk management during FTY-treatment.