Gender-Dependent HLA-DR-Restricted Epitopes Identified from Herpes Simplex Virus Type 1 Glycoprotein D

Zhang, Xiuli; Castelli, Florence; Zhu, Xiaoming; Wu, Michael; Maillère, Bernard; BenMohamed, Lbachir

doi:10.1128/cvi.00123-08

Cited by 61 publications

(51 citation statements)

References 85 publications

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“…Moreover, animal studies show that male mice, which are more resistant to EAE, produce more T H 2 cytokines than do female mice, whereas female mice, which are more susceptible, produce more T H 1 cytokines than do male mice 38. Recently, it was shown that vaccine efficacy against HSV-1 also is gender-dependent 39. These differences between male and female mice were attributed to differential IL-2 production in the absence of differences in IL-4.…”

Section: Resultsmentioning

confidence: 99%

Optic Neuritis in Different Strains of Mice by a Recombinant HSV-1 Expressing Murine Interleukin-2

Zandian

Belisle

Mott

et al. 2009

Invest. Ophthalmol. Vis. Sci.

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Purpose The authors have shown previously that a recombinant HSV-1 that constitutively expresses two copies of murine IL-2 (HSV-IL-2) induces demyelination by activated CD8+ T cells in the brain and spinal cord of ocularly infected female BALB/c mice. The present study was conducted to determine whether the ocular infection with this recombinant virus induces optic neuritis independent of virus dose, major histocompatibility complex (MHC) background, or sex. Methods Female BALB/c, C57BL/6, SJL/6, and 129SVE mice and male BALB/c mice were ocularly infected with different doses of recombinant HSV-IL-2 virus. Demyelination of optic nerves in infected mice was monitored histologically using Luxol fast blue staining and by measurement of visual-evoked cortical potentials (VECPs). Results Both focal and diffuse regions of demyelination of the optic nerves were observed in the HSV-IL-2–infected mice as early as day 10 after infection and as late as day 60 after infection (the final experimental time point) in all strains of mice tested. Optic nerve demyelination was not observed in control mice ocularly infected with HSV-IL-4 or wild-type HSV-1. VECP responses were delayed significantly in the HSV-IL-2–infected mice compared with mice infected with control viruses. Conclusions The results demonstrate for the first time that a combination of viral infection and constitutive expression of IL-2, but not IFN-γ or IL-4, can result in demyelination and visual impairment in the optic nerves of ocularly infected mice.

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Section: Resultsmentioning

confidence: 99%

Optic Neuritis in Different Strains of Mice by a Recombinant HSV-1 Expressing Murine Interleukin-2

Zandian

Belisle

Mott

et al. 2009

Invest. Ophthalmol. Vis. Sci.

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“…The four immunodominant gB responder peptides (i.e., gB 161-175, gB 166-180, gB 661-675 , and gB 666-680 ), as well as four nonresponder control peptides (i.e., gB 871-895, gB 886-900 , and gB [890][891][892][893][894][895][896][897][898][899][900][901][902][903][904] ), were synthesized and tested in vitro for binding to seven soluble HLA-DR molecules (Table 1). This panel of available HLA-DR molecules consists of the most common HLA class II haplotypes, regardless of ethnicity (78). The relative binding capacity (IC 50 [nanomolar]) for each peptide was calculated as the concentration of competitor peptide required to inhibit 50% of the binding of an allele-specific biotinylated peptide (indicator peptide), as described in Materials and Methods.…”

Section: Prevalence Of Gb Epitope-specific Ifn-␥-producing Cd4mentioning

confidence: 99%

“…The relative binding capacity (IC 50 [nanomolar]) for each peptide was calculated as the concentration of competitor peptide required to inhibit 50% of the binding of an allele-specific biotinylated peptide (indicator peptide), as described in Materials and Methods. Based on an upper threshold of 250 nM, which characterizes high-affinity peptide binders (11,78), gB 161-175, gB 166-180 , gB 661-675 , and gB 666-680 bound to three or more different HLA-DR molecules, while the remaining peptide epitopes did not bind to any of the HLA-DR molecules tested. This suggests that the gB 161-175, gB 166-180 , gB 661-675 , and gB 666-680 peptide epitopes contain at least one universal T-cell epitope or several overlapping epitopes presented by multiple HLA-DR molecules.…”

Section: Prevalence Of Gb Epitope-specific Ifn-␥-producing Cd4mentioning

confidence: 99%

Asymptomatic Human CD4⁺Cytotoxic T-Cell Epitopes Identified from Herpes Simplex Virus Glycoprotein B

Chentoufi

Binder

Berka

et al. 2008

J Virol

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The identification of "asymptomatic" (i.e., protective) epitopes recognized by T cells from herpes simplex virus (HSV)-seropositive healthy individuals is a prerequisite for an effective vaccine. Using the PepScan epitope mapping strategy, a library of 179 potential peptide epitopes (15-mers overlapping by 10 amino acids) was identified from HSV type 1 (HSV-1) glycoprotein B (gB), an antigen that induces protective immunity in both animal models and humans. Eighteen groups (G1 to G18) of 10 adjacent peptides each were first screened for T-cell antigenicity in 38 HSV-1-seropositive but HSV-2-seronegative individuals. Individual peptides within the two immunodominant groups (i.e., G4 and G14) were further screened with T cells from HLA-DRgenotyped and clinically defined symptomatic (n ‫؍‬ 10) and asymptomatic (n ‫؍‬ 10) HSV-1-seropositive healthy individuals. Peptides gB [161][162][163][164][165][166][167][168][169][170][171][172][173][174][175] ؉ T cells from symptomatic patients preferentially recognized gB 661-675 (P < 0.0001). Thus, we identified three previously unrecognized CD4؉ CTL peptide epitopes in HSV-1 gB. Among these, gB 166-180 and gB 666-680 appear to be "asymptomatic" peptide epitopes and therefore should be considered in the design of future herpes vaccines.Herpes simplex virus types 1 and 2 (HSV-1 and HSV-2) are ubiquitous viruses that infect a majority of people worldwide (3,22,68). Shedding of reactivated HSV is estimated to occur at rates of 3 to 28% in adults who harbor latent HSV in their sensory neurons (32,(66)(67)(68). However, the vast majority of these individuals do not experience recurrent herpetic disease and are designated "asymptomatic patients" (22,40,68). In contrast, in some individuals (symptomatic patients), reactivation of latent virus leads to induction of "pathogenic" HSVspecific CD4 ϩ and CD8 ϩ T cells (22, 68) and recurrent disease, ranging from rare episodes occurring every 5 to 10 years to outbreaks occurring monthly or even more frequently among a small proportion of subjects (22,26,60). Interestingly, for genital herpes, symptomatic and asymptomatic patients have similar virus shedding rates (68). It is likely that the same is true for ocular and oro-facial herpes, since shedding rates in tears and saliva of asymptomatic individuals have been reported to be as high as 33.5% (22,29,40,42). Latently infected patients are at risk of developing severe immunopathology, such as blinding herpetic stromal keratitis (HSK) (primarily due to HSV-1), painful genital ulcerations (primarily due to HSV-2), and in rare cases, fatal HSV encephalitis (reviewed in reference 72).Considering the wealth of data addressing the role of T cells in animal models, it is surprising how few reports explore the immunologic basis of symptomatic and asymptomatic HSV infections in humans. The HSV-1-specific CD4 ϩ T-cell responses in the cornea are much more likely to cause pathology than those in the genital tract or anus/buttocks region. Indeed, the involvement of CD4 ϩ T cells that produce Th1 cyt...

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“…Although many HLA-A*0201-restricted epitopes have been identified from HSV-1 and HSV-2 protein antigens, a question of practical importance is the translation of these pre-clinical findings based solely on HLA-0201-restricted epitopes, for the development of a universal vaccine for a genetically heterogeneous human population [17, 27, 202-205]. In an attempt to develop a universal T cell epitope-based vaccine, and since CD8 + T cells appear to be crucial effectors of protective immunity against HSV-1 and HSV-2 infections [14, 24, 25, 27, 43-54], past-decade research from our laboratory has focused on two strategies: (1) identifying HLA-restricted epitopes on herpes protein antigens that are strongly recognized by human CD8 + T cell from seropositive “asymptomatic” individuals; and (2) immunization of “humanized” HLA transgenic animal models (mice and rabbits) with antigenic epitopes to determine their immunogenicity and protective efficacy against ocular and genital herpes infection and disease. In our ongoing prophylactic and therapeutic herpes vaccine program, we have already successfully identified several “symptomatic” and “asymptomatic” CD8 + T cell epitopes and have demonstrated pathogenic vs. protective efficacy in “humanized” HLA-A*0201 transgenic animal models [24, 43, 44, 158].…”

Section: Resultsmentioning

confidence: 99%

“…Differences between the groups were identified by ANOVA, multiple comparison procedures, as we previously described [14, 24, 25, 27, 43-54]. Statistical analysis also included Fisher’s exact test and multivariate analyses, using logistic and linear regression models.…”

Section: Methodsmentioning

confidence: 99%

Associations of HLA-A, HLA-B and HLA-C alleles frequency with prevalence of herpes simplex virus infections and diseases across global populations: Implication for the development of an universal CD8+ T-cell epitope-based vaccine

et al. 2014

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A significant portion of the world’s population is infected with herpes simplex virus type 1 and/or type 2 (HSV-1 and/or HSV-2), that cause a wide range of diseases including genital herpes, oro-facial herpes, and the potentially blinding ocular herpes. While the global prevalence and distribution of HSV-1 and HSV-2 infections cannot be exactly established, the general trends indicate that: (i) HSV-1 infections are much more prevalent globally than HSV-2; (ii) Over half billion people worldwide are infected with HSV-2; (iii) the sub-Saharan African populations account for a disproportionate burden of genital herpes infections and diseases; (iv) the dramatic differences in the prevalence of herpes infections between regions of the world appear to be associated with differences in the frequencies of human leukocyte antigen (HLA) alleles. The present report: (i) analyzes the prevalence of HSV-1 and HSV-2 infections across various regions of the world; (ii) analyzes potential associations of common HLA-A, HLA-B and HLA-C alleles with the prevalence of HSV-1 and HSV-2 infections in the Caucasoid, Oriental, Hispanic and Black major populations; and (iii) discusses how our recently developed HLA-A, HLA-B, and HLA-C transgenic/H-2 class I null mice will help validate HLA/herpes prevalence associations. Overall, high prevalence of herpes infection and disease appears to be associated with high frequency of HLA-A*24, HLA-B*27, HLA-B*53 and HLA-B*58 alleles. In contrast, low prevalence of herpes infection and disease appears to be associated with high frequency of HLA-B*44 allele. The finding will aid in developing a T-cell epitope-based universal herpes vaccine and immunotherapy.

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Gender-Dependent HLA-DR-Restricted Epitopes Identified from Herpes Simplex Virus Type 1 Glycoprotein D

Cited by 61 publications

References 85 publications

Optic Neuritis in Different Strains of Mice by a Recombinant HSV-1 Expressing Murine Interleukin-2

Optic Neuritis in Different Strains of Mice by a Recombinant HSV-1 Expressing Murine Interleukin-2

Asymptomatic Human CD4⁺Cytotoxic T-Cell Epitopes Identified from Herpes Simplex Virus Glycoprotein B

Associations of HLA-A, HLA-B and HLA-C alleles frequency with prevalence of herpes simplex virus infections and diseases across global populations: Implication for the development of an universal CD8+ T-cell epitope-based vaccine

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Gender-Dependent HLA-DR-Restricted Epitopes Identified from Herpes Simplex Virus Type 1 Glycoprotein D

Cited by 61 publications

References 85 publications

Optic Neuritis in Different Strains of Mice by a Recombinant HSV-1 Expressing Murine Interleukin-2

Optic Neuritis in Different Strains of Mice by a Recombinant HSV-1 Expressing Murine Interleukin-2

Asymptomatic Human CD4+Cytotoxic T-Cell Epitopes Identified from Herpes Simplex Virus Glycoprotein B

Associations of HLA-A, HLA-B and HLA-C alleles frequency with prevalence of herpes simplex virus infections and diseases across global populations: Implication for the development of an universal CD8+ T-cell epitope-based vaccine

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Asymptomatic Human CD4⁺Cytotoxic T-Cell Epitopes Identified from Herpes Simplex Virus Glycoprotein B