Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine

Jing, Lichen; Haas, Juergen; Chong, Tiana M.; Bruckner, Joseph J.; Dann, Greg C.; Dong, Lichun; Marshak, Joshua O.; McClurkan, Christopher L.; Yamamoto, Tori N.; Bailer, Susanne M.; Laing, Kerry J.; Wald, Anna; Verjans, Georges M. G. M.; Koelle, David M.

doi:10.1172/jci60556

Cited by 90 publications

(169 citation statements)

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“…Antigen and epitope mapping. To map the antigen specificity of the CD4 ϩ T cells in genital biopsy specimens, we used the HSV-2 ORFeome, a tool which can be used to study proliferative responses to all HSV-2 open reading frames and which allows dissection of antigen-specific T cell responses (21). We observed reactivity to several HSV-2 antigens (range, 3 to 18) in lesion biopsy specimens in three of three participants who had HSV-specific cells detected from genital biopsy specimens (see Table S2 in the supplemental material).…”

Section: Resultsmentioning

confidence: 99%

“…Autologous peripheral blood mononuclear cells (PBMCs) labeled with carboxyfluorescein diacetate succinimidyl diester (CFSE) were used as antigen-presenting cells (APC) at a 1:1 ratio with expanded bulk skin lymphocyte responders as previously described (20). Brefeldin A was added at 1 h, cells were labeled for CD3 and CD4, and intracellular gamma interferon (IFN-␥), tumor necrosis factor alpha (TNF-␣), and interleukin-2 (IL-2) were measured at 6 h as previously described (21). A FACSantoflow cytometer (BD Biosciences) with FlowJo software (Tree Star) was used for determinations performed by gating on lymphocyte forward and side scatter, excluding CFSE-positive cells.…”

Section: Laboratory Methods (I) Hsv Pcrmentioning

confidence: 99%

“…For biopsy specimens from participants who had HSV-specific CD4 ϩ T cells, we used a complete CD4 ϩ T cell HSV-2 protein set, termed the HSV-2 open reading frame (ORF)eome, to test for proliferative responses to individual HSV proteins, as described for HSV-1 (21). Briefly, bulk expanded CD4 ϩ lymphocytes, autologous irradiated PBMCs used as APC, and recombinant HSV-2 proteins were plated in duplicate in 96-well U-bottom plates.…”

Section: Laboratory Methods (I) Hsv Pcrmentioning

confidence: 99%

“…[ 3 H]thymidine incorporation was measured after 3 days to detect cell proliferation. The criterion for positivity for each antigen was set as the mean plus 2.1 times the standard deviation of the [ 3 H]thymidine incorporation for 54 negativecontrol antigens (21). In one participant tested with both the HSV-1 and HSV-2 ORFeomes, CD4 ϩ cells in both lesion and asymptomatic biopsy specimens showed reactivity to VP16.…”

Section: Laboratory Methods (I) Hsv Pcrmentioning

confidence: 99%

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Virologic and Immunologic Evidence of Multifocal Genital Herpes Simplex Virus 2 Infection

Johnston

Zhu

Jing

et al. 2014

J Virol

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Genital herpes simplex virus (HSV) reactivation is thought to be anatomically and temporally localized, coincident with limited ganglionic infection. Short, subclinical shedding episodes are the most common form of HSV-2 reactivation, with host clearance mechanisms leading to rapid containment. The anatomic distribution of shedding episodes has not been characterized. To precisely define patterns of anatomic reactivation, we divided the genital tract into a 22-region grid and obtained daily swabs for 20 days from each region in 28 immunocompetent, HSV-2-seropositive persons. HSV was detected via PCR, and sites of asymptomatic HSV shedding were subjected to a biopsy procedure within 24 h. CD4؉ and CD8 ؉ T cells were quantified by immunofluorescence, and HSV-specific CD4 ؉ T cells were identified by intracellular cytokine cytometry. HSV was detected in 868 (7%) of 11,603 genital swabs at a median of 12 sites per person (range, 0 to 22). Bilateral HSV detection occurred on 83 (67%) days with shedding, and the median quantity of virus detected/day was associated with the number of sites positive (P < 0.001). In biopsy specimens of asymptomatic shedding sites, we found increased numbers of CD8 ؉ T cells compared to control tissue (27 versus 13 cells/mm 2 , P ‫؍‬ 0.03) and identified HSV-specific CD4 ؉ T cells. HSV reactivations emanate from widely separated anatomic regions of the genital tract and are associated with a localized cellular infiltrate that was demonstrated to be HSV specific in 3 cases. These data provide evidence that asymptomatic HSV-2 shedding contributes to chronic inflammation throughout the genital tract. IMPORTANCEThis detailed report of the anatomic patterns of genital HSV-2 shedding demonstrates that HSV-2 reactivation can be detected at multiple bilateral sites in the genital tract, suggesting that HSV establishes latency throughout the sacral ganglia. In addition, genital biopsy specimens from sites of asymptomatic HSV shedding have increased numbers of CD8 ؉ T cells compared to control tissue, and HSV-specific CD4 ؉ T cells are found at sites of asymptomatic shedding. These findings suggest that widespread asymptomatic genital HSV-2 shedding is associated with a targeted host immune response and contributes to chronic inflammation throughout the genital tract. H erpes simplex virus 2 (HSV-2) infects over 500 million people worldwide (1) and is the leading cause of genital ulcer disease (2) and increases the risk of HIV acquisition (3). Herpetic genital ulcers in the immunocompetent person are localized with respect to time and anatomic site (4), consistent with reactivation of virus from the ganglion innervating this region. However, most HSV genital shedding is subclinical, with rapid onset and clearance (5, 6). Such subclinical reactivation may be more widespread in the genital area (7), consistent with frequent leakage of virus into the genital skin and mucosa with localized host containment (8, 9). Mathematical models suggest that observed shedding patterns are the result of ove...

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Section: Resultsmentioning

confidence: 99%

Section: Laboratory Methods (I) Hsv Pcrmentioning

confidence: 99%

Section: Laboratory Methods (I) Hsv Pcrmentioning

confidence: 99%

Section: Laboratory Methods (I) Hsv Pcrmentioning

confidence: 99%

See 2 more Smart Citations

Virologic and Immunologic Evidence of Multifocal Genital Herpes Simplex Virus 2 Infection

Johnston

Zhu

Jing

et al. 2014

J Virol

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“…Some were studied previously (Supplemental Table I). HSV-1 immunity was studied in participants 21 and 23 (25, 27), zoster vaccine immunity in participants 1, 2, 3, 4, and 26 (16), T-cell responses to HSV-2 in subjects 30-34 (15), and drug reactions in subject 35 (28). Subjects 6-19 and 26-29 were genetically confirmed HSV-1-infected monozygotic twins (29, 30), with consecutively numbers denoting twin pairs.…”

Section: Methodsmentioning

confidence: 99%

Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses

Jing

Laing

Dong

et al. 2016

The Journal of Immunology

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The alphaherpesvirinae subfamily includes HSV types 1 and 2 and the sequence-divergent pathogen varicella zoster virus (VZV). T cells, controlled by TCR and HLA molecules that tolerate limited epitope amino acid variation, might cross-react between these microbes. We show that memory PBMC expansion with either HSV or VZV enriches for CD4 T cell lines that recognize the other agent at the whole virus, protein, and peptide levels, consistent with bi-directional cross-reactivity. HSV-specific CD4 T cells recovered from HSV seronegative persons can be partially explained by such VZV cross-reactivity. HSV-1-reactive CD8 T cells also cross-react with VZV-infected cells, full-length VZV proteins, and VZV peptides, and kill VZV-infected dermal fibroblasts. Mono- and cross-reactive CD8 T cells use distinct TCRB CDR3 sequences. Cross-reactivity to VZV is reconstituted by cloning and expressing TCRA/TCRB receptors from T-cells that are initially isolated using HSV reagents. Overall, we define 13 novel CD4 and CD8 HSV-VZV cross-reactive epitopes and strongly imply additional cross-reactive peptide sets. Viral proteins can harbor both CD4 and CD8 HSV/VZV cross-reactive epitopes. Quantitative estimates of HSV/VZV cross-reactivity for both CD4 and CD8 T cells vary from 10-50%. Based on these findings, we hypothesize host herpesvirus immune history may influence the pathogenesis and clinical outcome of subsequent infections or vaccinations for related pathogens, and that cross-reactive epitopes and TCRs may be useful for multi-alphaherpesvirus vaccine design and adoptive cellular therapy.

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Viral Shedding 1 Year Following First-Episode Genital HSV-1 Infection

Johnston

Magaret

Son

et al. 2022

JAMA

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ImportanceHerpes simplex virus type 1 (HSV-1) is the leading cause of first-episode genital herpes in many countries.ObjectiveTo inform counseling messages regarding genital HSV-1 transmission, oral and genital viral shedding patterns among persons with first-episode genital HSV-1 infection were assessed. The trajectory of the development of HSV-specific antibody and T-cell responses was also characterized.Design, Setting, and ParticipantsProspective cohort followed up for up to 2 years, with 82 participants followed up between 2013 and 2018. Participants were recruited from sexual health and primary care clinics in Seattle, Washington. Persons with laboratory-documented first-episode genital HSV-1 infection, without HIV infection or current pregnancy, were referred for enrollment.ExposuresFirst-episode genital HSV-1 infection.Main Outcomes and MeasuresGenital and oral HSV-1 shedding and lesion rates at 2 months, 11 months, and up to 2 years after initial genital HSV-1 infection. Participants self-collected oral and genital swabs for HSV polymerase chain reaction testing for 30 days at 2 and 11 months and up to 2 years after diagnosis of genital HSV-1. Blood samples were collected at serial time points to assess immune responses to HSV-1. Primary HSV-1 infection was defined as absent HSV antibody at baseline or evolving antibody profile using the University of Washington HSV Western Blot. HSV-specific T-cell responses were detected using interferon γ enzyme-linked immunospot.ResultsAmong the 82 participants, the median (range) age was 26 (16-64) years, 54 (65.9%) were women, and 42 (51.2%) had primary HSV-1 infection. At 2 months, HSV-1 was detected from the genital tract in 53 participants (64.6%) and in the mouth in 24 participants (29.3%). Genital HSV-1 shedding was detected on 275 of 2264 days (12.1%) at 2 months and declined significantly to 122 of 1719 days (7.1%) at 11 months (model-predicted rate, 6.2% [95% CI, 4.3%-8.9%] at 2 months vs 3.2% [95% CI, 1.8%-5.7%] at 11 months; relative risk, 0.52 [95% CI, 0.29-0.93]). Genital lesions were rare, reported on 65 of 2497 days (2.6%) at 2 months and 72 of 1872 days (3.8%) at 11 months. Oral HSV-1 shedding was detected on 88 of 2247 days (3.9%) at 2 months. Persons with primary HSV-1 infection had a higher risk of genital shedding compared with those with nonprimary infection (model-predicted rate, 7.9% [95% CI, 5.4%-11.7%] vs 2.9% [95% CI, 1.7%-5.0%]; relative risk, 2.75 [95% CI, 1.40-5.44]). Polyfunctional HSV-specific CD4+ and CD8+ T-cell responses were maintained during the follow-up period.Conclusions and RelevanceGenital HSV-1 shedding was frequent after first-episode genital HSV-1, particularly among those with primary infection, and declined rapidly during the first year after infection.

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Cross-presentation and genome-wide screening reveal candidate T cells antigens for a herpes simplex virus type 1 vaccine

Cited by 90 publications

References 94 publications

Virologic and Immunologic Evidence of Multifocal Genital Herpes Simplex Virus 2 Infection

Virologic and Immunologic Evidence of Multifocal Genital Herpes Simplex Virus 2 Infection

Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses

Viral Shedding 1 Year Following First-Episode Genital HSV-1 Infection

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