scispace - formally typeset
Search or ask a question
Author

Kaori Sango

Bio: Kaori Sango is an academic researcher from Harvard University. The author has contributed to research in topics: Epitope & CTL*. The author has an hindex of 6, co-authored 6 publications receiving 960 citations.
Topics: Epitope, CTL*, Cytotoxic T cell, Viral load, Antigen

Papers
More filters
Journal ArticleDOI
TL;DR: Factors that contribute to the immunogenicity of these highly targeted and relatively conserved sequences in HIV that may represent promising vaccine candidates for ethnically heterogeneous populations are identified.
Abstract: Although there is increasing evidence that virus-specific cytotoxic-T-lymphocyte (CTL) responses play an important role in the control of human immunodeficiency virus (HIV) replication in vivo, only scarce CTL data are available for the ethnic populations currently most affected by the epidemic. In this study, we examined the CD8+-T-cell responses in African-American, Caucasian, Hispanic, and Caribbean populations in which clade B virus dominates and analyzed the potential factors influencing immune recognition. Total HIV-specific CD8+-T-cell responses were determined by enzyme-linked immunospot assays in 150 HIV-infected individuals by using a clade B consensus sequence peptide set spanning all HIV proteins. A total of 88% of the 410 tested peptides were recognized, and Nef- and Gag-specific responses dominated the total response for each ethnicity in terms of both breadth and magnitude. Three dominantly targeted regions within these proteins that were recognized by >90% of individuals in each ethnicity were identified. Overall, the total breadth and magnitude of CD8+-T-cell responses correlated with individuals’ CD4 counts but not with viral loads. The frequency of recognition for each peptide was highly correlated with the relative conservation of the peptide sequence, the presence of predicted immunoproteasomal cleavage sites within the C-terminal half of the peptide, and a reduced frequency of amino acids that impair binding of optimal epitopes to the restricting class I molecules. The present study thus identifies factors that contribute to the immunogenicity of these highly targeted and relatively conserved sequences in HIV that may represent promising vaccine candidates for ethnically heterogeneous populations.

292 citations

Journal ArticleDOI
TL;DR: Analysis of cytotoxic T lymphocyte responses restricted by HLA-B*1503 suggests that subdominant responses can contribute to in vivo viral control and that high HLA allele frequencies may drive the elimination ofSubdominant yet effective epitopes from circulating viral populations.
Abstract: Despite limited data supporting the superiority of dominant over subdominant responses, immunodominant epitopes represent the preferred vaccine candidates. To address the function of subdominant responses in human immunodeficiency virus infection, we analyzed cytotoxic T lymphocyte responses restricted by HLA-B*1503, a rare allele in a cohort infected with clade B, although common in one infected with clade C. HLA-B*1503 was associated with reduced viral loads in the clade B cohort but not the clade C cohort, although both shared the immunodominant response. Clade B viral control was associated with responses to several subdominant cytotoxic T lymphocyte epitopes, whereas their clade C variants were less well recognized. These data suggest that subdominant responses can contribute to in vivo viral control and that high HLA allele frequencies may drive the elimination of subdominant yet effective epitopes from circulating viral populations.

238 citations

Journal ArticleDOI
TL;DR: The data support the important role of HLA-B alleles in antiviral immunity and afford a better understanding of the factors contributing to inter- and intraindividual immunodominance.
Abstract: Immunodominance is variably used to describe either the most frequently detectable response among tested individuals or the strongest response within a single individual, yet factors determining either inter- or intraindividual immunodominance are still poorly understood. More than 90 individuals were tested against 184 HIV- and 92 EBV-derived, previously defined CTL epitopes. The data show that HLA-B-restricted epitopes were significantly more frequently recognized than HLA-A- or HLA-C-restricted epitopes. HLA-B-restricted epitopes also induced responses of higher magnitude than did either HLA-A- or HLA-C-restricted epitopes, although this comparison only reached statistical significance for EBV epitopes. For both viruses, the magnitude and frequency of recognition were correlated with each other, but not with the epitope binding affinity to the restricting HLA allele. The presence or absence of HIV coinfection did not impact EBV epitope immunodominance patterns significantly. Peptide titration studies showed that the magnitude of responses was associated with high functional avidity, requiring low concentration of cognate peptide to respond in in vitro assays. The data support the important role of HLA-B alleles in antiviral immunity and afford a better understanding of the factors contributing to inter- and intraindividual immunodominance.

164 citations

Journal ArticleDOI
TL;DR: Functional assays confirmed the frequent recognition of HLA class I‐restricted T cell epitopes on several alternative alleles across HLAclass I supertypes and encoded on different class I loci, suggesting promiscuous binding of T helper epitopes to MHC class II molecules.
Abstract: Promiscuous binding of T helper epitopes to MHC class II molecules has been well established, but few examples of promiscuous class I-restricted epitopes exist To address the extent of promiscuity of HLA class I peptides, responses to 242 well-defined viral epitopes were tested in 100 subjects regardless of the individuals' HLA type Surprisingly, half of all detected responses were seen in the absence of the originally reported restricting HLA class I allele, and only 3% of epitopes were recognized exclusively in the presence of their original allele Functional assays confirmed the frequent recognition of HLA class I-restricted T cell epitopes on several alternative alleles across HLA class I supertypes and encoded on different class I loci These data have significant implications for the understanding of MHC class I-restricted antigen presentation and vaccine development

125 citations

Journal ArticleDOI
TL;DR: This work constructed lentiviral vectors encoding an HIV-1-specific TCR α and TCR β chains cloned from a CTL clone specific for an HIV Gag epitope, SL9, as a single transcript linked with a self-cleaving peptide and demonstrated that transduction with this lentivirus efficiently converted primary human CD8 lymphocytes into HIV- 1-specific CTLs with potent in vitro and in vivo HIV-2-specific activity.
Abstract: The human immunodeficiency virus type 1 (HIV-1)-specific CD8 cytotoxic T-lymphocyte (CTL) response plays a critical role in controlling HIV-1 replication. Augmenting this response should enhance control of HIV-1 replication and stabilize or improve the clinical course of the disease. Although cytomegalovirus (CMV) or Epstein-Barr virus (EBV) infection in immunocompromised patients can be treated by adoptive transfer of ex vivo-expanded CMV- or EBV-specific CTLs, adoptive transfer of ex vivo-expanded, autologous HIV-1-specific CTLs had minimal effects on HIV-1 replication, likely a consequence of the inherently compromised qualitative function of HIV-1-specific CTLs derived from HIV-1-infected individuals. We hypothesized that this limitation could be circumvented by using as an alternative source of HIV-1-specific CTLs, autologous peripheral CD8 + T lymphocytes whose antigen specificity is redirected by transduction with lentiviral vectors encoding HIV-1-specific T-cell receptor (TCR) α and β chains, an approach used successfully in cancer therapy. To efficiently convert peripheral CD8 lymphocytes into HIV-1-specific CTLs that potently suppress in vivo HIV-1 replication, we constructed lentiviral vectors encoding the HIV-1-specific TCR α and TCR β chains cloned from a CTL clone specific for an HIV Gag epitope, SL9, as a single transcript linked with a self-cleaving peptide. We demonstrated that transduction with this lentiviral vector efficiently converted primary human CD8 lymphocytes into HIV-1-specific CTLs with potent in vitro and in vivo HIV-1-specific activity. Using lentiviral vectors encoding an HIV-1-specific TCR to transform peripheral CD8 lymphocytes into HIV-1-specific CTLs with defined specificities represents a new immunotherapeutic approach to augment the HIV-1-specific immunity of infected patients.

86 citations


Cited by
More filters
Journal ArticleDOI
TL;DR: A comprehensive analysis of the 160 dominant CD8+ T-cell responses in 578 untreated HIV-infected individuals from KwaZulu-Natal, South Africa suggested the existence of both effective immune responses and responses lacking demonstrable biological impact in chronic HIV infection.
Abstract: Selection of T-cell vaccine antigens for chronic persistent viral infections has been largely empirical. To define the relationship, at the population level, between the specificity of the cellular immune response and viral control for a relevant human pathogen, we performed a comprehensive analysis of the 160 dominant CD8(+) T-cell responses in 578 untreated HIV-infected individuals from KwaZulu-Natal, South Africa. Of the HIV proteins targeted, only Gag-specific responses were associated with lowering viremia. Env-specific and Accessory/Regulatory protein-specific responses were associated with higher viremia. Increasing breadth of Gag-specific responses was associated with decreasing viremia and increasing Env breadth with increasing viremia. Association of the specific CD8(+) T-cell response with low viremia was independent of HLA type and unrelated to epitope sequence conservation. These population-based data, suggesting the existence of both effective immune responses and responses lacking demonstrable biological impact in chronic HIV infection, are of relevance to HIV vaccine design and evaluation.

1,039 citations

Journal ArticleDOI
TL;DR: This experiment of nature provides a system to advance understanding of immunological homeostasis in humans, illustrating how data obtained from the study of EBV have wider significance to the immunological community.
Abstract: Epstein-Barr virus (EBV) provides a useful model to study cellular immunity to a genetically stable, persistent human virus. Different sets of proteins expressed during EBV's lytic and cell transforming infections induce qualitatively different cellular immune responses. The factors governing immunodominance hierarchies and the biological effectiveness of these different responses are now being revealed. Analysis of infectious mononucleosis (IM), a clinical syndrome that can arise during primary EBV infection, has allowed the evolution of the responses to be tracked over time, giving an understanding of the immune response kinetics and of those determinants affecting selection into memory. Furthermore, following IM, expression of the receptor for the homeostatic cytokine IL-15 on NK and T cells is lost within these individuals. This experiment of nature provides a system to advance understanding of immunological homeostasis in humans, illustrating how data obtained from the study of EBV have wider significance to the immunological community.

736 citations

Journal ArticleDOI
TL;DR: It is shown that B27-KK10–specific CD8+ T cells are characterized by polyfunctional capabilities, increased clonal turnover, and superior functional avidity, which constitute the basis for effective control of HIV-1 replication.
Abstract: The key attributes of CD8+ T cell protective immunity in human immunodeficiency virus (HIV) infection remain unclear. We report that CD8+ T cell responses specific for Gag and, in particular, the immunodominant p24 epitope KK10 correlate with control of HIV-1 replication in human histocompatibility leukocyte antigen (HLA)–B27 patients. To understand further the nature of CD8+ T cell–mediated antiviral efficacy, we performed a comprehensive study of CD8+ T cells specific for the HLA-B27–restricted epitope KK10 in chronic HIV-1 infection based on the use of multiparametric flow cytometry together with molecular clonotypic analysis and viral sequencing. We show that B27-KK10–specific CD8+ T cells are characterized by polyfunctional capabilities, increased clonal turnover, and superior functional avidity. Such attributes are interlinked and constitute the basis for effective control of HIV-1 replication. These data on the features of effective CD8+ T cells in HIV infection may aid in the development of successful T cell vaccines.

707 citations

Journal ArticleDOI
TL;DR: It is shown that the NetMHCpan-2.0 method can accurately predict binding to uncharacterized HLA molecules, including HLA-C and Hla-G, and is demonstrated to accurately predict peptide binding to chimpanzee and macaque MHC class I molecules.
Abstract: Binding of peptides to major histocompatibility complex (MHC) molecules is the single most selective step in the recognition of pathogens by the cellular immune system. The human MHC genomic region (called HLA) is extremely polymorphic comprising several thousand alleles, each encoding a distinct MHC molecule. The potentially unique specificity of the majority of HLA alleles that have been identified to date remains uncharacterized. Likewise, only a limited number of chimpanzee and rhesus macaque MHC class I molecules have been characterized experimentally. Here, we present NetMHCpan-2.0, a method that generates quantitative predictions of the affinity of any peptide–MHC class I interaction. NetMHCpan-2.0 has been trained on the hitherto largest set of quantitative MHC binding data available, covering HLA-A and HLA-B, as well as chimpanzee, rhesus macaque, gorilla, and mouse MHC class I molecules. We show that the NetMHCpan-2.0 method can accurately predict binding to uncharacterized HLA molecules, including HLA-C and HLA-G. Moreover, NetMHCpan-2.0 is demonstrated to accurately predict peptide binding to chimpanzee and macaque MHC class I molecules. The power of NetMHCpan-2.0 to guide immunologists in interpreting cellular immune responses in large out-bred populations is demonstrated. Further, we used NetMHCpan-2.0 to predict potential binding peptides for the pig MHC class I molecule SLA-1*0401. Ninety-three percent of the predicted peptides were demonstrated to bind stronger than 500 nM. The high performance of NetMHCpan-2.0 for non-human primates documents the method’s ability to provide broad allelic coverage also beyond human MHC molecules. The method is available at http://www.cbs.dtu.dk/services/NetMHCpan .

699 citations

Journal ArticleDOI
TL;DR: This review focuses on exploring the hypothesis that PD‐1 ligation induces distinct signals during various stages of immune‐cell differentiation, and describing models to dissect the function of thePD‐1 cytoplasmic tail using primary cells in the absence of agonist antibodies.
Abstract: Programmed death-1 (PD-1) is a cell surface molecule that regulates the adaptive immune response Engagement of PD-1 by its ligands PD-L1 or PD-L2 transduces a signal that inhibits T-cell proliferation, cytokine production, and cytolytic function While a great deal is known concerning the biologic roles PD-1 plays in regulating the primary immune response and in T-cell exhaustion, comparatively little is known regarding how PD-1 ligation alters signaling pathways PD-1 ligation is known to inhibit membrane-proximal T-cell signaling events, while ligation of the related inhibitory molecule cytotoxic T-lymphocyte antigen-4 appears to target more downstream signaling pathways A major obstacle to an in-depth understanding of PD-1 signaling is the lack of physiologic models in which to study signal transduction This review focuses on: (i) signaling pathways altered by PD-1 ligation, (ii) factors recruited upon PD-1 phosphorylation, and (iii) exploring the hypothesis that PD-1 ligation induces distinct signals during various stages of immune-cell differentiation Lastly, we describe models to dissect the function of the PD-1 cytoplasmic tail using primary cells in the absence of agonist antibodies

673 citations