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Jost, Stephanie

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Jost

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Stephanie

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Jost, Stephanie
Author's Publications: search.filters.isAuthorOfPublication.c01c5b24-bafa-4ee1-9e98-4a108e35e80c

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    Antigen-specific NK cell memory in rhesus macaques
    (2015) Reeves, R. Keith; Li, Haiying; Jost, Stephanie; Blass, Eryn; Li, Hualin; Schafer, Jamie L.; Varner, Valerie; Manickam, Cordelia; Eslamizar, Leila; Altfeld, Marcus; von Andrian-Werburg, Ulrich; Barouch, Dan
    Natural killer (NK) cells have traditionally been considered nonspecific components of innate immunity, but recent studies have shown features of antigen-specific memory in murine NK cells. However, it has remained unclear whether this phenomenon also exists in primates. Compared to NK cells from uninfected macaques, we found splenic and hepatic NK cells from SHIV-SF162P3- and SIVmac251-infected animals specifically lysed Gag- and Env-pulsed dendritic cells (DCs) in an NKG2-dependent fashion. Moreover, splenic and hepatic NK cells from Ad26-vaccinated macaques efficiently lysed antigen-matched but not antigen-mismatched targets 5 years post-vaccination. These data demonstrate that robust, durable, antigen-specific NK cell memory can be induced in primates following both infection and vaccination, and could be important for vaccines against HIV-1 and other pathogens.
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    Increased frequencies of CD8+CD57+ T cells are associated with antibody neutralization breadth against HIV in viraemic controllers
    (International AIDS Society, 2016) Palmer, Christine D; Romero-Tejeda, Marisol; Scully, Eileen P; Lockhart, Ainsley; Seaman, Michael; Goldenthal, Ariel; Piechocka-Trocha, Alicja; Walker, Bruce; Chibnik, Lori; Jost, Stephanie; Porichis, Filippos
    Introduction: An effective prophylactic vaccine against HIV will need to elicit antibody responses capable of recognizing and neutralizing rapidly evolving antigenic regions. The immunologic milieu associated with development of neutralizing antibody breadth remains to be fully defined. In this study, we sought to identify immunological signatures associated with neutralization breadth in HIV controllers. We applied an immune monitoring approach to analyze markers of T cell and myeloid cell activation by flow cytometry, comparing broad neutralizers with low- and non-neutralizers using multivariate and univariate analyses. Methods: Antibody neutralization breadth was determined, and cryopreserved peripheral blood mononuclear cells were stained for T cell and myeloid cell activation markers. Subjects were grouped according to neutralization breadth, and T cell and myeloid cell activation was analyzed by partial least squares discriminant analysis to determine immune signatures associated with high neutralization breadth. Results: We show that neutralization breadth in HIV viraemic controllers (VC) was strongly associated with increased frequencies of CD8+CD57+ T cells and that this association was independent of viral load, CD4 count and time since HIV diagnosis. Conclusions: Our data show elevated frequencies of CD8+CD57+ T cells in VC who develop neutralization breadth against HIV. This immune signature could serve as a potential biomarker of neutralization breadth and should be further investigated in other HIV-positive cohorts and in HIV vaccine trials.
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    P10-01. MHC Class I Chain-related Protein A Shedding in Chronic HIV-1 Infection is Associated with Profound NK Cell Dysfunction
    (BioMed Central, 2009) Nolting, A; Luteijn, R; Carrington, M; Rihn, S; Toth, I; Faetkenheuer, G; Hartmann, P; Dugast, Anne-Sophie; Kane, Kay; Jost, Stephanie; Altfeld, Marcus; Alter, Galit
    Background: Natural killer (NK) cells play a critical role in the host defense against viral infections. However, chronic HIV-1 infection is associated with an accumulation of dysfunctional NK cells that poorly control viral replication. The underlying mechanism for this NK cell mediated dysfunction is not well understood. Certain tumors directly evade NK cell mediated detection by dampening NK cell activity via the downregulation of NKG2D, a potent activating NK cell receptor, via the release of soluble NKG2D-ligands. This results in a potent suppression of NK cell function. We hypothesized that NKG2D-mediated cytotoxicity in chronic HIV-1 infection is impaired and associated with shedding of NKG2D ligand MICA (sMICA). Methods: Flow cytometric analysis was performed on 100 subjects to quantify NKG2D expression and NK cell functional responses (cell activation (CD69) and degranulation (CD107a)) following stimulation with K562 (MHCdevoid, NKG2D target) and 221 cells (MHC devoid, non-NKG2D target). Additionally, the level of MICA and matrix metalloproteases (MMP, involved in NKG2D-ligand shedding) were quantified by quantitative PCR. Finally, the level of secreted MICA was measured by ELISA. Results: Here we show for the first time that chronic HIV-1 infection is associated with a specific defect in NKG2D-mediated activation of NK cells, due to alterations in both the expression and transcription of NKG2D in NK cells. Reduced NKG2D expression was associated with elevated levels of the NKG2D-ligand, MICA, in patient sera, likely released by HIV infected CD4+ T cells due to enhanced enzymatic cleavage, by MMPs, of this stress inducible molecule from the surface of the target cell. Conclusion: Thus, HIV is able to indirectly suppress NK cell mediated functional recognition of HIV-infected CD4+ T cells by enhancing NKG2D-ligand secretion into the peripheral circulation resulting in a profound impairment of NK cell function.