Antigen sensitivity is a major determinant of CD8(+) T-cell polyfunctionality and HIV-suppressive activity
ABSTRACT CD8(+) T cells are major players in the immune response against HIV. However, recent failures in the development of T cell-based vaccines against HIV-1 have emphasized the need to reassess our basic knowledge of T cell-mediated efficacy. CD8(+) T cells from HIV-1-infected patients with slow disease progression exhibit potent polyfunctionality and HIV-suppressive activity, yet the factors that unify these properties are incompletely understood. We performed a detailed study of the interplay between T-cell functional attributes using a bank of HIV-specific CD8(+) T-cell clones isolated in vitro; this approach enabled us to overcome inherent difficulties related to the in vivo heterogeneity of T-cell populations and address the underlying determinants that synthesize the qualities required for antiviral efficacy. Conclusions were supported by ex vivo analysis of HIV-specific CD8(+) T cells from infected donors. We report that attributes of CD8(+) T-cell efficacy against HIV are linked at the level of antigen sensitivity. Highly sensitive CD8(+) T cells display polyfunctional profiles and potent HIV-suppressive activity. These data provide new insights into the mechanisms underlying CD8(+) T-cell efficacy against HIV, and indicate that vaccine strategies should focus on the induction of HIV-specific T cells with high levels of antigen sensitivity to elicit potent antiviral efficacy.
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ABSTRACT: Despite progress toward understanding the correlates of protective T cell immunity in HIV infection, the optimal approach to Ag delivery by vaccination remains uncertain. We characterized two immunodominant CD8 T cell populations generated in response to immunization of BALB/c mice with a replication-deficient adenovirus serotype 5 vector expressing the HIV-derived Gag and Pol proteins at equivalent levels. The Gag-AI9/H-2K d epitope elicited high-avidity CD8 T cell populations with architecturally diverse clonotypic repertoires that displayed potent lytic activity in vivo. In contrast, the Pol-LI9/H-2D d epitope elicited motif-constrained CD8 T cell repertoires that displayed lower levels of physical avidity and lytic activity despite equivalent measures of overall clonality. Although low-dose vaccination enhanced the functional profiles of both epitope-specific CD8 T cell populations, greater polyfunctionality was apparent within the Pol-LI9/H-2D d specificity. Higher proportions of central memory-like cells were present after low-dose vaccination and at later time points. However, there were no noteworthy phenotypic differences between epitope-specific CD8 T cell populations across vaccine doses or time points. Collectively, these data indicate that the functional and phenotypic properties of vaccine-induced CD8 T cell populations are sensitive to dose manipulation, yet constrained by epitope specificity in a clonotype-dependent manner.The Journal of Immunology 12/2014; 193:5626-5636. DOI:10.4049/jimmunol.1401017 · 5.36 Impact Factor
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ABSTRACT: In this cross-sectional study we evaluated T-cell responses using several assays to determine immune correlates of HIV control that distinguish untreated viraemic controllers (VC) from noncontrollers (NC) with similar CD4 counts. Samples were taken from 65 ART-naïve chronically HIV-infected VC and NC from Thailand with matching CD4 counts in the normal range (>450 cells/μl). We determined HIVp24-specific T-cell responses using standard Interferon-gamma (IFNγ) ELISpot assays, and compared the functional quality of HIVp24-specific CD8+ T-cell responses using polychromatic flow cytometry. Finally, in vitro HIV suppression assays were performed to evaluate directly the activity of CD8+ T cells in HIV control. Autologous CD4+ T cells were infected with primary patient-derived HIV isolates and the HIV suppressive activity of CD8+ T cells was determined after co-culture, measuring production of HIVp24 Ag by ELISA. The HIVp24-specific T-cell responses of VC and NC could not completely be differentiated through measurement of IFNγ-producing cells using ELISpot assays, nor by the absolute cell numbers of polyfunctional HIVp24-specific CD8+ T cells. However, in vitro HIV suppression assays showed clear differences between VC and NC. HIV suppressive activity, mediated by either ex vivo unstimulated CD8+ T cells or HIVp24-specific T-cell lines, was significantly greater using cells from VC than NC cells. Additionally, we were able to demonstrate a significant correlation between the level of HIV suppressive activity mediated by ex vivo unstimulated CD8+ T cells and plasma viral load (pVL) (Spearman r = -0.7345, p = 0.0003). This study provides evidence that in vitro HIV suppression assays are the most informative in the functional evaluation of CD8+ T-cell responses and can distinguish between VC and NC.PLoS ONE 03/2015; 10(3):e0118871. DOI:10.1371/journal.pone.0118871 · 3.53 Impact Factor
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ABSTRACT: Specific CD8(+) T cells (CTLs) play an important role in resolving protracted infection with hepatitis B and C virus in humans and lymphocytic choriomeningitis virus (LCMV) in mice. The contribution of individual CTL specificities to chronic virus control, as well as epitope-specific patterns in timing and persistence of antiviral selection pressure, remain, however, incompletely defined. To monitor and characterize the antiviral efficacy of individual CTL specificities throughout the course of chronic infection, we coinoculated mice with a mixture of wild-type LCMV and genetically engineered CTL epitope-deficient mutant virus. A quantitative longitudinal assessment of viral competition revealed that mice continuously exerted CTL selection pressure on the persisting virus population. The timing of selection pressure characterized individual epitope specificities, and its magnitude varied considerably between individual mice. This longitudinal assessment of "antiviral efficacy" provides a novel parameter to characterize CTL responses in chronic viral infection. It demonstrates remarkable perseverance of all antiviral CTL specificities studied, thus raising hope for therapeutic vaccination in the treatment of persistent viral diseases. Copyright © 2015 by The American Association of Immunologists, Inc.