Antigen Load and Viral Sequence Diversification Determine the Functional Profile of HIV-1–Specific CD8+ T Cells

Partners AIDS Research Center, Infectious Disease Unit, Massachusetts General Hospital and Division of AIDS, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS Medicine (Impact Factor: 14.43). 05/2008; 5(5):e100. DOI: 10.1371/journal.pmed.0050100
Source: PubMed


Virus-specific CD8(+) T lymphocytes play a key role in the initial reduction of peak viremia during acute viral infections, but display signs of increasing dysfunction and exhaustion under conditions of chronic antigen persistence. It has been suggested that virus-specific CD8(+) T cells with a "polyfunctional" profile, defined by the capacity to secrete multiple cytokines or chemokines, are most competent in controlling viral replication in chronic HIV-1 infection. We used HIV-1 infection as a model of chronic persistent viral infection to investigate the process of exhaustion and dysfunction of virus-specific CD8(+) T cell responses on the single-epitope level over time, starting in primary HIV-1 infection.
We longitudinally analyzed the polyfunctional epitope-specific CD8(+) T cell responses of 18 patients during primary HIV-1 infection before and after therapy initiation or sequence variation in the targeted epitope. Epitope-specific CD8(+) T cells responded with multiple effector functions to antigenic stimulation during primary HIV-1 infection, but lost their polyfunctional capacity in response to antigen and up-regulated programmed death 1 (PD-1) expression with persistent viremic infection. This exhausted phenotype significantly decreased upon removal of stimulation by antigen, either in response to antiretroviral therapy or by reduction of epitope-specific antigen load in the presence of ongoing viral replication, as a consequence of in vivo selection of cytotoxic T lymphocyte escape mutations in the respective epitopes. Monofunctionality increased in CD8(+) T cell responses directed against conserved epitopes from 49% (95% confidence interval 27%-72%) to 76% (56%-95%) (standard deviation [SD] of the effect size 0.71), while monofunctionality remained stable or slightly decreased for responses directed against escaped epitopes from 61% (47%-75%) to 56% (42%-70%) (SD of the effect size 0.18) (p < 0.05).
These data suggest that persistence of antigen can be the cause, rather than the consequence, of the functional impairment of virus-specific T cell responses observed during chronic HIV-1 infection, and underscore the importance of evaluating autologous viral sequences in studies aimed at investigating the relationship between virus-specific immunity and associated pathogenesis.

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Available from: Chanson J Brumme, Oct 04, 2015
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    • "Increases in the proportions of T FH CD4 T cells, which produce IL-21, have been reported during chronic LCMV, HBV, and HIV infections (Crawford et al., 2014; Fahey et al., 2011; Li et al., 2013; Streeck et al., 2008). IL-6 is another cytokine that, in collaboration with IL-21, contributes to the generation of T FH cells and the generation of robust humoral immunity (Dienz et al., 2009; Eto et al., 2011; Karnowski et al., 2012). "
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    ABSTRACT: Although robust and highly effective anti-viral T cells contribute to the clearance of many acute infections, viral persistence is associated with the development of functionally inferior, exhausted, T cell responses. Exhaustion develops in a step-wise and progressive manner, ranges in severity, and can culminate in the deletion of the anti-viral T cells. This disarming of the response is consequential as it compromises viral control and potentially serves to dampen immune-mediated damage. Exhausted T cells are unable to elaborate typical anti-viral effector functions. They are characterized by the sustained upregulation of inhibitory receptors and display a gene expression profile that distinguishes them from prototypic effector and memory T cell populations. In this review we discuss the properties of exhausted T cells; the virological and immunological conditions that favor their development; the cellular and molecular signals that sustain the exhausted state; and strategies for preventing and reversing exhaustion to favor viral control. Copyright © 2014 Elsevier Inc. All rights reserved.
    Virology 01/2015; 361. DOI:10.1016/j.virol.2014.12.033 · 3.32 Impact Factor
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    • "Moreover, the frequency of PD-1+ T cells was higher in tumor-bearing LN than peripheral blood in cattle with lymphoma, and the same tendency was reported in patients with metastatic melanoma [37]. Immune tolerance by PD-1 expression in T cells follows T-cell activation by continued epitope recognition in peripheral lymphoid tissue [38-42]. Thus, one can speculate that most tumor infiltrated PD-1+ T cells could be specific for lymphoma cells, and present tumor-associated antigen, but fail to be activated properly by the PD-1/PD-L1 pathway, resulting in the immune evasion of BLV-induced lymphoma cells. "
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    ABSTRACT: Programmed death-1 (PD-1) is a known immunoinhibitory receptor that contributes to immune evasion of various tumor cells and pathogens causing chronic infection, such as bovine leukemia virus (BLV) infection. First, in this study, to establish a method for the expression and functional analysis of bovine PD-1, hybridomas producing monoclonal antibodies (mAb) specific for bovine PD-1 were established. Treatment with these anti-PD-1 mAb enhanced interferon-gamma (IFN-gamma) production of bovine peripheral blood mononuclear cells (PBMC). Next, to examine whether PD-1 blockade by anti-PD-1 mAb could upregulate the immune reaction during chronic infection, the expression and functional analysis of PD-1 in PBMC isolated from BLV-infected cattle with or without lymphoma were performed using anti-PD-1 mAb. The frequencies of both PD-1+ CD4+ T cells in blood and lymph node and PD-1+ CD8+ T cells in lymph node were higher in BLV-infected cattle with lymphoma than those without lymphoma or control uninfected cattle. PD-1 blockade enhanced IFN-gamma production and proliferation and reduced BLV-gp51 expression and B-cell activation in PBMC from BLV-infected cattle in response to BLV-gp51 peptide mixture. These data show that anti-bovine PD-1 mAb could provide a new therapy to control BLV infection via upregulation of immune response.
    Veterinary Research 07/2013; 44(1):59. DOI:10.1186/1297-9716-44-59 · 2.82 Impact Factor
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    • "The expression of Programmed Death 1 (PD-1) has been linked to CD8 T cell dysfunction, especially defective cytokine production and impaired in vitro proliferation capacity, in human/simian immunodeficiency virus (HIV/SIV) infection (1–5). Chronic T cell receptor (TCR)-mediated stimulation is necessary to maintain high PD-1 expression on SIV-specific CD8 T cells (6) and, most likely, on HIV-specific CD8 T cells (7). Furthermore, PD-1 expression correlates with reduced antigen-specific CD8 T cell survival in vitro (8–10). "
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    ABSTRACT: Programmed Death-1 (PD-1) expression by human/simian immunodeficiency virus (HIV/SIV)-specific CD8 T cells has been associated with defective cytokine production and reduced in vitro proliferation capacity. However, the cellular mechanisms that sustain PD-1(high) virus-specific CD8 T cell responses during chronic infection are unknown. Here, we show that the PD-1(high) phenotype is associated with accelerated in vivo CD8 T cell turnover in SIV-infected rhesus macaques, especially within the SIV-specific CD8 T cell pool. Mathematical modeling of BrdU labeling dynamics demonstrated a significantly increased generation rate of PD-1(high) compared to PD-1(low) CD8 T cells in all memory compartments. Simultaneous analysis of Ki67 and BrdU kinetics revealed a complex in vivo turnover profile, whereby only a small fraction of PD-1(high) cells, but virtually all PD-1(low) cells, returned to rest after activation. Similar kinetics operated in both chronic and acute SIV infection. Our data suggest that the persistence of PD-1(high) SIV-specific CD8 T cells in chronic infection is maintained in vivo by a mechanism involving high production coupled to high disappearance.
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