Memory Cytotoxic T Cell Responses to Viral Tegument and Regulatory Proteins Encoded by Open Reading Frames 4, 10, 29, and 62 of Varicella-Zoster Virus

Arvin, Ann M.; Sharp, Margaret; Moir, Melinda S.; Kinchington, Paul R.; Sadeghizadeh, Majid; Ruyechan, William T.; Hay, John

doi:10.1089/088282402760312377

Cited by 45 publications

(34 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For the ␣-herpesvirus bovine herpesvirus 1 (BHV-1), strong CD8 ϩ T cell responses directed against various glycoproteins were found in BHV-1-infected calves (21). Following reactivation of varicella-zoster virus, high frequencies of circulating T cells recognizing a variety of structural and regulatory proteins were found (22,23). Strong CD8 ϩ T cell responses to the tegument phosphoprotein 65 and the immediate early protein 1 were found for the ␤-herpesvirus human CMV (24,25).…”

Section: Ajor Histocompatibility Complex Class I-mediated Peptide Pmentioning

confidence: 99%

The Varicellovirus UL49.5 Protein Blocks the Transporter Associated with Antigen Processing (TAP) by Inhibiting Essential Conformational Transitions in the 6+6 Transmembrane TAP Core Complex

Verweij

Koppers-Lalić

Loch

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

TAP translocates virus-derived peptides from the cytosol into the endoplasmic reticulum, where the peptides are loaded onto MHC class I molecules. This process is crucial for the detection of virus-infected cells by CTL that recognize the MHC class I-peptide complexes at the cell surface. The varicellovirus bovine herpesvirus 1 encodes a protein, UL49.5, that acts as a potent inhibitor of TAP. UL49.5 acts in two ways, as follows: 1) by blocking conformational changes of TAP required for the translocation of peptides into the endoplasmic reticulum, and 2) by targeting TAP1 and TAP2 for proteasomal degradation. At present, it is unknown whether UL49.5 interacts with TAP1, TAP2, or both. The contribution of other members of the peptide-loading complex has not been established. Using TAP-deficient cells reconstituted with wild-type and recombinant forms of TAP1 and TAP2, TAP was defined as the prime target of UL49.5 within the peptide-loading complex. The presence of TAP1 and TAP2 was required for efficient interaction with UL49.5. Using deletion mutants of TAP1 and TAP2, the 6+6 transmembrane core complex of TAP was shown to be sufficient for UL49.5 to interact with TAP and block its function. However, UL49.5-induced inhibition of peptide transport was most efficient in cells expressing full-length TAP1 and TAP2. Inhibition of TAP by UL49.5 appeared to be independent of the presence of other peptide-loading complex components, including tapasin. These results demonstrate that UL49.5 acts directly on the 6+6 transmembrane TAP core complex of TAP by blocking essential conformational transitions required for peptide transport.

show abstract

Section: Ajor Histocompatibility Complex Class I-mediated Peptide Pmentioning

confidence: 99%

The Varicellovirus UL49.5 Protein Blocks the Transporter Associated with Antigen Processing (TAP) by Inhibiting Essential Conformational Transitions in the 6+6 Transmembrane TAP Core Complex

Verweij

Koppers-Lalić

Loch

et al. 2008

The Journal of Immunology

View full text Add to dashboard Cite

show abstract

“…VZV-specific CD4 ϩ T cells synthesize Th1-like cytokines, such as interleukin-2 (IL-2) and gamma interferon (IFN-␥) (22,31), and are capable of major histocompatibility complex class II-restricted cytotoxicity (6,13,16,20). T-cell antigen specificity has been addressed in a number of studies which have documented reactivity to several VZV proteins, including the regulatory and structural proteins encoded by open reading frame 10 (ORF10), ORF62, and ORF63 (5,28) and glycoproteins gB, gC, gE, and gI (3,6,19). One study documented the existence of ORF4 protein-specific cytotoxic T lymphocytes, which were again detectable only following expansion in vitro (5).…”

mentioning

confidence: 99%

“…T-cell antigen specificity has been addressed in a number of studies which have documented reactivity to several VZV proteins, including the regulatory and structural proteins encoded by open reading frame 10 (ORF10), ORF62, and ORF63 (5,28) and glycoproteins gB, gC, gE, and gI (3,6,19). One study documented the existence of ORF4 protein-specific cytotoxic T lymphocytes, which were again detectable only following expansion in vitro (5). Despite evidence supporting a role for T cells in the control of VZV replication, there are no previous studies that have identified VZV-specific CD4 ϩ T-cell epitopes.…”

mentioning

confidence: 99%

“…Despite evidence supporting a role for T cells in the control of VZV replication, there are no previous studies that have identified VZV-specific CD4 ϩ T-cell epitopes. The VZV genome comprises more than 70 unique open reading frames which encode proteins that are potential targets for the host immune system (2,5,14). ORF4 encodes a 51-kDa IE protein (15,23,26).…”

mentioning

confidence: 99%

See 1 more Smart Citation

Persistent High Frequencies of Varicella-Zoster Virus ORF4 Protein-Specific CD4⁺T Cells after Primary Infection

Jones

Black

Malavige

et al. 2006

J Virol

View full text Add to dashboard Cite

Open reading frame 4 (ORF4) of varicella-zoster virus (VZV) encodes an immediate-early protein that is believed to be important for viral infectivity and establishing latency. Evidence suggests that VZV-specific T cells are crucial in the control of viral replication, but there are no data addressing the existence of potential ORF4 protein-specific CD4؉ T cells. We tested the hypothesis that VZV ORF4 protein-specific CD4 ؉ T cells could be identified and characterized within the peripheral blood of healthy immune donors following primary infection. Gamma interferon (IFN-␥) immunosorbent assays were used to screen peripheral blood mononuclear cells obtained from healthy seropositive donors for responses to overlapping ORF4 peptides, viral lysate, and live vaccine. High frequencies of ORF4 protein-specific T cells were detected ex vivo in individuals up to 52 years after primary infection. Several immunogenic regions of the ORF4 protein were identified, including a commonly recognized epitope which was restricted through HLA-DRB1*07. Total ORF4 protein-specific responses comprised 19.7% and 20.7% of the total lysate and vaccine responses, respectively, and were dominated by CD4 ؉ T cells. Indeed, CD4 ؉ T cells were found to dominate the overall virus-specific IFN-␥ cellular immune response both ex vivo and after expansion in vitro. In summary, we have identified an ORF4 protein as a novel target antigen for persistent VZV-specific CD4 ؉ T cells, with implications for disease pathogenesis and future vaccine development.

show abstract

“…Both viral proteins are large (∼1300 aa long) and contain a DNA binding and a large C-terminal transactivator domain that are both highly conserved among alphaherpesvirinae of diverse animal species (28,40,63). Previous studies showed that viral tegument proteins, including VZV IE62 and HSV-1 ICP4, are immunoprevalent targets of aHHV-specific CD4 and CD8 T cells in blood of healthy HSV-1-and/or VZV-infected adults (29,(64)(65)(66), lesions of genital herpes patients (67), affected eyes of herpetic uveitis and keratitis patients (18)(19)(20)68), and at the site of HSV-1 latency in human trigeminal ganglia (69). The identification of a HLA-DR promiscuous and broadly recognized CD4 T cell epitope, located within VZV IE62 and HSV-1 ICP4, underscores the immunogenicity of both viral proteins as T cell targets.…”

Section: Discussionmentioning

confidence: 99%

Functional Characterization of Ocular-Derived Human Alphaherpesvirus Cross-Reactive CD4 T Cells

Ouwendijk¹,

Geluk

Smits³

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

Intraocular varicella-zoster virus (VZV) and HSV type 1 (HSV-1) infections cause sight-threatening uveitis. The disease is characterized by an intraocular inflammatory response involving herpesvirus-specific T cells. T cell reactivity to the noncausative human alphaherpesvirus (αHHV) is commonly detected in the affected eyes of herpetic uveitis patients, suggesting the role of cross-reactive T cells in the disease. This study aimed to identify and functionally characterize intraocular human alphaherpesvirus cross-reactive T cells. VZV protein immediate early 62 (IE62), which shares extensive homology with HSV ICP4, is a previously identified T cell target in VZV uveitis. Two VZV-specific CD4 T cell clones (TCC), recovered from the eye of a VZV uveitis patient, recognized the same IE62918–927 peptide using different TCR and HLA-DR alleles. The IE62918–927 peptide bound with high affinity to multiple HLA-DR alleles and was recognized by blood-derived T cells of 5 of 17 HSV-1/VZV-seropositive healthy adults but not in cord blood donors (n = 5). Despite complete conservation of the IE62 epitope in the orthologous protein ICP4 of HSV-1 and HSV-2, the TCC recognized VZV and HSV-1– but not HSV-2–infected B cells. This was not attributed to proximal epitope-flanking amino acid polymorphisms in HSV-2 ICP4. Notably, VZV/HSV-1 cross-reactive CD4 T cells controlled VZV but not HSV-1 infection of human primary retinal pigment epithelium (RPE) cells. In conclusion, we report on the first VZV/HSV-1 cross-reactive CD4 T cell epitope, which is HLA-DR promiscuous and immunoprevalent in coinfected individuals. Moreover, ocular-derived peptide-specific CD4 TCC controlled VZV but not HSV-1 infection of RPE cells, suggesting that HSV-1 actively inhibits CD4 T cell activation by infected human RPE cells.

show abstract

Memory Cytotoxic T Cell Responses to Viral Tegument and Regulatory Proteins Encoded by Open Reading Frames 4, 10, 29, and 62 of Varicella-Zoster Virus

Cited by 45 publications

References 34 publications

The Varicellovirus UL49.5 Protein Blocks the Transporter Associated with Antigen Processing (TAP) by Inhibiting Essential Conformational Transitions in the 6+6 Transmembrane TAP Core Complex

The Varicellovirus UL49.5 Protein Blocks the Transporter Associated with Antigen Processing (TAP) by Inhibiting Essential Conformational Transitions in the 6+6 Transmembrane TAP Core Complex

Persistent High Frequencies of Varicella-Zoster Virus ORF4 Protein-Specific CD4⁺T Cells after Primary Infection

Functional Characterization of Ocular-Derived Human Alphaherpesvirus Cross-Reactive CD4 T Cells

Contact Info

Product

Resources

About

Memory Cytotoxic T Cell Responses to Viral Tegument and Regulatory Proteins Encoded by Open Reading Frames 4, 10, 29, and 62 of Varicella-Zoster Virus

Cited by 45 publications

References 34 publications

The Varicellovirus UL49.5 Protein Blocks the Transporter Associated with Antigen Processing (TAP) by Inhibiting Essential Conformational Transitions in the 6+6 Transmembrane TAP Core Complex

The Varicellovirus UL49.5 Protein Blocks the Transporter Associated with Antigen Processing (TAP) by Inhibiting Essential Conformational Transitions in the 6+6 Transmembrane TAP Core Complex

Persistent High Frequencies of Varicella-Zoster Virus ORF4 Protein-Specific CD4+T Cells after Primary Infection

Functional Characterization of Ocular-Derived Human Alphaherpesvirus Cross-Reactive CD4 T Cells

Contact Info

Product

Resources

About

Persistent High Frequencies of Varicella-Zoster Virus ORF4 Protein-Specific CD4⁺T Cells after Primary Infection