Article

Betts, M.R. et al. HIV nonprogressors preferentially maintain highly functional HIV-specific CD8+ T cells. Blood 107, 4781-4789

University of Alabama at Birmingham, Birmingham, Alabama, United States
Blood (Impact Factor: 10.43). 07/2006; 107(12):4781-9. DOI: 10.1182/blood-2005-12-4818
Source: PubMed

ABSTRACT Establishing a CD8(+) T cell-mediated immune correlate of protection in HIV disease is crucial to the development of vaccines designed to generate cell-mediated immunity. Historically, neither the quantity nor breadth of the HIV-specific CD8(+) T-cell response has correlated conclusively with protection. Here, we assess the quality of the HIV-specific CD8(+) T-cell response by measuring 5 CD8(+) T-cell functions (degranulation, IFN-gamma, MIP-1beta, TNF-alpha, and IL-2) simultaneously in chronically HIV-infected individuals and elite nonprogressors. We find that the functional profile of HIV-specific CD8(+) T cells in progressors is limited compared to that of nonprogressors, who consistently maintain highly functional CD8(+) T cells. This limited functionality is independent of HLA type and T-cell memory phenotype, is HIV-specific rather than generalized, and is not effectively restored by therapeutic intervention. Whereas the total HIV-specific CD8(+) T-cell frequency did not correlate with viral load, the frequency and proportion of the HIV-specific T-cell response with highest functionality inversely correlated with viral load in the progressors. Thus, rather than quantity or phenotype, the quality of the CD8(+) T-cell functional response serves as an immune correlate of HIV disease progression and a potential qualifying factor for evaluation of HIV vaccine efficacy.

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    • "TNF expansion could be responsible for a high degree of inflammation, which could be linked to tissue damage and lung lesions rather than protection and control of the pathogen. According to what has been assumed to be the hallmark of a protective CD4 + T-cell response in various models of human viral infections [28] [34] [35], we found a significantly higher proportion of multifunctional IFN-í µí»¾ + IL-2 + TNF-í µí»¼ + CD4 + T cells in subjects with LTBI, which are able to control Mtb replication compared with those with current TB disease, in which CD4 + T cells secreting TNF alone dominated the Mtb-specific response. As regards the CD8 + T-cell compartment, Rozot et al. [36] [37] recently indicated that Mtb-specific CD8 + Tcell responses can be detected predominantly in patients with active TB as compared to LTBI subjects, suggesting a correlation between CD8 + T-cell responses and high antigen burden [19] [38]. "
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    DESCRIPTION: Mono- and multifunctional specific CD4+ and CD8+ T-cell responses were evaluated to improve the immune-based detection of active tuberculosis (TB) and latent infection (LTBI). We applied flow cytometry to investigate cytokines profile (IFN-𝛾, TNF-𝛼, and IL-2) of T cells after stimulation with TB antigens in 28 TB-infected subjects (18 active TB and 10 LTBI) and 10 uninfected controls. Cytokines production by CD4+ T cells at single-cell levelswas higher in TB-infected subjects than uninfected controls (𝑃 <0.0001). Assigning to activated CD4+ T cells, producing any of the three cytokines, a cut-off >0.45%, it was possible to differentiate TB-infected (>0.45%) by uninfected subjects (<0.45%). Among TB-infected subjects, the frequencies of multifunctional CD4+ T cells, simultaneously producing all 3 cytokines, are lower in active TB than LTBI subjects (𝑃 = 0.003). Thus, assigning to triple positive CD4+ T cells a cut-off<0.182%, TB-infected individuals could be classified as active TB subjects (<0.182%) or LTBI subjects (>0.182%). The magnitude of CD8+ T-cell responses showed no differences between active TB and LTBI. Multifunctional CD4+ T-cell responses could have the potential to identify at single time point subjects without TB infection and patients having active or latent TB.
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    • "TNF expansion could be responsible for a high degree of inflammation, which could be linked to tissue damage and lung lesions rather than protection and control of the pathogen. According to what has been assumed to be the hallmark of a protective CD4 + T-cell response in various models of human viral infections [28] [34] [35], we found a significantly higher proportion of multifunctional IFN-í µí»¾ + IL-2 + TNF-í µí»¼ + CD4 + T cells in subjects with LTBI, which are able to control Mtb replication compared with those with current TB disease, in which CD4 + T cells secreting TNF alone dominated the Mtb-specific response. As regards the CD8 + T-cell compartment, Rozot et al. [36] [37] recently indicated that Mtb-specific CD8 + Tcell responses can be detected predominantly in patients with active TB as compared to LTBI subjects, suggesting a correlation between CD8 + T-cell responses and high antigen burden [19] [38]. "
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    DESCRIPTION: Hindawi Publishing Corporation Journal of Immunology Research Article ID 217287
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    • "In contrast, there is a growing consensus that durable control among patients bearing protective alleles is associated with superior CD8 + T-cell function (reviewed in Hersperger et al., 2011). Among the CD8 + T-cell functions that have most consistently distinguished LTNP/EC from progressors are increased polyfunctionality, proliferation, loading of cytotoxic proteins, virus suppressive ability and cytotoxic capacity (Betts et al., 2006; Ferre et al., 2009; Hersperger et al., 2010; Migueles et al., 2002, 2008; Saez-Cirion et al., 2007; Zimmerli et al., 2005). "
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    ABSTRACT: Understanding natural immunologic control over Human Immunodeficiency Virus (HIV)-1 replication, as occurs in rare long-term nonprogressors/elite controllers (LTNP/EC), should inform the design of efficacious HIV vaccines and immunotherapies. Durable control in LTNP/EC is likely mediated by highly functional virus-specific CD8+ T-cells. Protective Human Leukocyte Antigen (HLA) class I alleles, like B*27 and B*57, are present in most, but not all LTNP/EC, providing an opportunity to investigate features shared by their HIV-specific immune responses. To better understand the contribution of epitope targeting and conservation to immune control, we compared the CD8+ T-cell specificity and function of B*27/57neg LTNP/EC (n = 23), B*27/57pos LTNP/EC (n = 23) and B*27/57neg progressors (n = 13). Fine mapping revealed 11 previously unreported immunodominant responses. Although B*27/57neg LTNP/EC did not target more highly conserved epitopes, their CD8+ T-cell cytotoxic capacity was significantly higher than progressors. Similar to B*27/57pos LTNP/EC, this superior cytotoxicity was mediated by preferential expansion of immunodominant responses and lysis through the predicted HLA. These findings suggest that increased CD8+ T-cell cytotoxic capacity is a common mechanism of control in most LTNP/EC regardless of HLA type. They also suggest that potent cytotoxicity can be mediated through various epitopes and HLA molecules and could, in theory, be induced in most people.
    01/2015; 79(1). DOI:10.1016/j.ebiom.2014.12.009
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