Broadly targeted CD8
            <sup>+</sup>
            T cell responses restricted by major histocompatibility complex E

Hansen, Scott G.; Wu, Helen L.; Burwitz, Benjamin J.; Hughes, Colette M.; Hammond, Katherine B.; Ventura, Abigail B.; Reed, Jason S.; Gilbride, Roxanne M.; Ainslie, Emily; Morrow, David W.; Ford, Julia C.; Selseth, Andrea N.; Pathak, Reesab; Malouli, Daniel; Legasse, Alfred W.; Axthelm, Michael K.; Nelson, Jay A.; Gillespie, Geraldine M.; Walters, Lucy; Brackenridge, Simon; Sharpe, Hannah; López, César A.; Früh, Klaus; Korber, Bette T.; McMichael, Andrew J.; Gnanakaran, S.; Sacha, Jonah B.; Picker, Louis J.

doi:10.1126/science.aac9475

Cited by 273 publications

(452 citation statements)

References 56 publications

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“…The role of MHC-E in both NK cell regulation and antigen presentation to CD8+ T cells is conserved in mice (29–34), but few studies have investigated MHC-E function in physiologically relevant NHP models. Recently, we described the induction of pathogen-specific MHC-E-restricted CD8+ T cell responses in rhesus macaques (RM, Macaca mulatta) after vaccination with rhesus cytomegalovirus (RhCMV)-based vaccine vectors (35), confirming the role of Mamu-E in antigen presentation to CD8+ T cells. RhCMV-based vaccination with SIV antigens (RhCMV/SIV) elicits SIV-specific, Mamu-E-restricted CD8+ T cells and results in robust control and clearance of SIV infection in approximately fifty percent of vaccinated rhesus macaques (36), suggesting pathogen-targeted MHC-E-restricted CD8+ T cells might serve as effective anti-viral immune responses.…”

Section: Introductionmentioning

confidence: 78%

“…The creation of single chain trimer constructs (SCTs) has been previously described in detail (35, 53). Briefly, each construct encodes a fusion protein of MHC-E signal peptide, peptide of interest, human β2M, the mature form of MHC-E of interest or Mamu-A1*001:01 (α1 through cytoplasmic domain), and EGFP connected by flexible linker regions ([GGGGS] X ).…”

Section: Methodsmentioning

confidence: 99%

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The Role of MHC-E in T Cell Immunity Is Conserved among Humans, Rhesus Macaques, and Cynomolgus Macaques

Wiseman

Hughes

et al. 2018

The Journal of Immunology

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Major histocompatibility complex E (MHC-E) is a highly conserved non-classical MHC-Ib molecule that predominantly binds and presents MHC-Ia leader sequence-derived peptides for natural killer cell regulation. However, MHC-E also binds pathogen-derived peptide antigens for presentation to CD8+ T cells. Given this role in adaptive immunity and its highly monomorphic nature in the human population, HLA-E is an attractive target for novel vaccine and immunotherapeutic modalities. Development of HLA-E-targeted therapies will require a physiologically relevant animal model that recapitulates HLA-E-restricted T cell biology. Here, we investigated MHC-E immunobiology in two common nonhuman primate species, Indian-origin rhesus macaques (RM) and Mauritian-origin cynomolgus macaques (MCM). Compared to humans and MCM, RM expressed a greater number of MHC-E alleles at both the population and individual level. Despite this difference, human, RM, and MCM MHC-E molecules were expressed at similar levels across immune cell subsets, equivalently up-regulated by viral pathogens, and bound and presented identical peptides to CD8+ T cells. Indeed, SIV-specific, Mamu-E-restricted CD8+ T cells from RM recognized antigenic peptides presented by all MHC-E molecules tested, including cross-species recognition of human and MCM SIV-infected CD4+ T cells. Thus, MHC-E is functionally conserved among humans, RM, and MCM, and both RM and MCM represent physiologically relevant animal models of HLA-E-restricted T cell immunobiology.

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Section: Introductionmentioning

confidence: 78%

Section: Methodsmentioning

confidence: 99%

The Role of MHC-E in T Cell Immunity Is Conserved among Humans, Rhesus Macaques, and Cynomolgus Macaques

Wiseman

Hughes

et al. 2018

The Journal of Immunology

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“…Similarly, a direct correlation between Gag-specific T cell responses prior to infection and control of acute viremia was found in DNA-vaccinated macaques (32). Others found that the inclusion of Gag in the vaccine was critical for the control of viremia using recombinant vesicular stomatitis virus (33,34), and recombinant human CMV (35,36) vaccines. We identified seven CE that represent 54% of the HIV-1 p24 Gag protein, and are found in nearly every HIV-1 (M group) strain observed to date throughout the world (19,(23)(24)(25).…”

mentioning

confidence: 99%

DNA Prime-Boost Vaccine Regimen To Increase Breadth, Magnitude, and Cytotoxicity of the Cellular Immune Responses to Subdominant Gag Epitopes of Simian Immunodeficiency Virus and HIV

Valentı́n

Dayton

et al. 2016

The Journal of Immunology

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HIV sequence diversity and the propensity of eliciting immunodominant responses targeting variable regions of the HIV proteome are hurdles in the development of an effective AIDS vaccine. An HIV-derived conserved element (CE) p24gag plasmid DNA (pDNA) vaccine is able to redirect immunodominant responses to otherwise subdominant and often more vulnerable viral targets. By homology to the HIV immunogen, seven CE were identified in SIV p27Gag. Analysis of 31 rhesus macaques vaccinated with full-length SIV gag pDNA showed inefficient induction (58% response rate) of cellular responses targeting these CE. In contrast, all 14 macaques immunized with SIV p27CE pDNA developed robust T cell responses recognizing CE. Vaccination with p27CE pDNA was also critical for the efficient induction and increased the frequency of Ag-specific T cells with cytotoxic potential (granzyme B+ CD107a+) targeting subdominant CE epitopes, compared with the responses elicited by the p57gag pDNA vaccine. Following p27CE pDNA priming, two booster regimens, gag pDNA or codelivery of p27CE+gag pDNA, significantly increased the levels of CE-specific T cells. However, the CE+gag pDNA booster vaccination elicited significantly broader CE epitope recognition, and thus, a more profound alteration of the immunodominance hierarchy. Vaccination with HIV molecules showed that CE+gag pDNA booster regimen further expanded the breadth of HIV CE responses. Hence, SIV/HIV vaccine regimens comprising CE pDNA prime and CE+gag pDNA booster vaccination significantly increased cytotoxic T cell responses to subdominant highly conserved Gag epitopes and maximized response breadth.

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“…On the other hand, Hansen et al 90 , 91 reported no protection from virus acquisition but found robust control of viremia in ∼half of the rCMV (SIV Gag) immunized macaques. A fundamental difference between our and the rCMV vaccine is that DNA vaccination induces T cell immunity using canonical MHC molecules, while certain rCMV vectors are able to elicit T cell immunity through the non-canonical MHC-E, 94 , 95 a feature that makes the rCMV vector induced responses unique. In a study designed to mimick elite controllers, Mudd et al 69 reported that vaccination of Mamu B*08 + macaques with recombinant yellow fever 17D (rYF17D)/rAd5 vectors expressing three Mamu B*08 restricted Nef and Vif CD8 epitopes resulted in efficient control of viremia.…”

Section: Discussionmentioning

confidence: 99%

Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques

Valentı́n

et al. 2018

Human Vaccines & Immunotherapeutics

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HIV sequence diversity and the propensity of eliciting immunodominant responses targeting inessential variable regions are hurdles in the development of an effective AIDS vaccine. We developed a DNA vaccine comprising conserved elements (CE) of SIV p27Gag and HIV-1 Env and found that priming vaccination with CE DNA is critical to efficiently overcome the dominance imposed by Gag and Env variable regions. Here, we show that DNA vaccinated macaques receiving the CE prime/CE+full-length DNA co-delivery booster vaccine regimens developed broad, potent and durable cytotoxic T cell responses targeting conserved protein segments of SIV Gag and HIV Env. Gag CE-specific T cells showed robust anamnestic responses upon infection with SIVmac239 which led to the identification of CE-specific cytotoxic lymphocytes able to recognize epitopes covering distinct CE on the surface of SIV infected cells in vivo. Though not controlling infection overall, we found an inverse correlation between Gag CE-specific CD8+ T cell responses and peak viremia. The T cell responses induced by the HIV Env CE immunogen were recalled in some animals upon SIV infection, leading to the identification of two cross-reactive epitopes between HIV and SIV Env based in sequence homology. These data demonstrate that a vaccine combining Gag and Env CE DNA subverted the normal immunodominance patterns, eliciting immune responses that included subdominant, highly conserved epitopes. These vaccine regimens augment cytotoxic T cell responses to highly conserved epitopes in the viral proteome and maximize response breadth. The vaccine-induced CE-specific T cells were expanded upon SIV infection, indicating that the predicted CE epitopes incorporated in the DNA vaccine are processed and exposed by infected cells in their natural context within the viral proteome.

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Broadly targeted CD8 ⁺ T cell responses restricted by major histocompatibility complex E

Cited by 273 publications

References 56 publications

The Role of MHC-E in T Cell Immunity Is Conserved among Humans, Rhesus Macaques, and Cynomolgus Macaques

The Role of MHC-E in T Cell Immunity Is Conserved among Humans, Rhesus Macaques, and Cynomolgus Macaques

DNA Prime-Boost Vaccine Regimen To Increase Breadth, Magnitude, and Cytotoxicity of the Cellular Immune Responses to Subdominant Gag Epitopes of Simian Immunodeficiency Virus and HIV

Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques

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Broadly targeted CD8 + T cell responses restricted by major histocompatibility complex E

Cited by 273 publications

References 56 publications

The Role of MHC-E in T Cell Immunity Is Conserved among Humans, Rhesus Macaques, and Cynomolgus Macaques

The Role of MHC-E in T Cell Immunity Is Conserved among Humans, Rhesus Macaques, and Cynomolgus Macaques

DNA Prime-Boost Vaccine Regimen To Increase Breadth, Magnitude, and Cytotoxicity of the Cellular Immune Responses to Subdominant Gag Epitopes of Simian Immunodeficiency Virus and HIV

Gag and env conserved element CE DNA vaccines elicit broad cytotoxic T cell responses targeting subdominant epitopes of HIV and SIV Able to recognize virus-infected cells in macaques

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Broadly targeted CD8 ⁺ T cell responses restricted by major histocompatibility complex E